Advertisement

Transforming Growth Factor-Beta in Prostate Cancer

Chapter
Part of the Protein Reviews book series (PRON, volume 16)

Abstract

TGF-βs are 25 kDa dimeric proteins that function through autocrine, paracrine, and endocrine mechanisms to regulate a diverse array of cellular and physiological processes in numerous tissues. Deregulation of TGF-β signaling is involved in the pathophysiology of prostate cancer. Central to normal prostate epithelial and stromal cell growth control mechanisms, TGF-β functions as a tumor suppressor and an important regulator of androgenic responses. Particularly striking, androgen withdrawal activates multiple components of the TGF-β signaling pathway in the normal prostate, which then partake in the ensuing apoptotic cell death response. Multiple discreet alterations in TGF-β signaling responses occur during the process of carcinogenesis and tumor progression, which contribute to the development of both metastatic disease and ultimately to castrate-resistant prostate cancer (CRPC). Despite its seemingly straightforward role as a tumor suppressor in the normal prostate, there is accumulating evidence supporting that the function of TGF-β “switches” to a tumor promoter during carcinogenesis/tumor progression. This represents what has now been coined the “TGF-β paradox,” the molecular and physiological basis for which remains incompletely defined. The TGF-β paradox also imposes inevitable complexities in therapeutic strategies involving TGF-β. However, recent advances provide significant promise for TGF-β as a prognostic marker and therapeutic target of prostate cancer (PCa).

This chapter provides a current overview of key components of the TGF-β signaling pathway. Starting with some historical perspective, the chapter highlights fundamentals of the TGF-β ligand structure, regulation of expression, storage, and activation. Next illustrated are the nuts and bolts of TGF-β receptor and Smad ­structure and function. A thorough perspective and mechanistic insight is provided on the current understanding in the field of TGF-β in normal and malignant prostate and state-of-the-art progress on TGF-β-based preclinical and clinical therapeutic opportunities.

Keywords

Androgen Receptor LNCaP Cell Prostate Intraepithelial Neoplasia Normal Prostate Epithelium Endogenous Androgen Receptor 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

The author is in debt for Dr. Donald Tindall’s excellent editorial help. This work was supported in part by NIH grants R01 CA134878 and P30 CA43703.

References

  1. 1.
    de Larco JE, Todaro GJ (1978) Growth factors from murine sarcoma virus-transformed cells. Proc Natl Acad Sci USA 75(8):4001–4005Google Scholar
  2. 2.
    Roberts AB, Frolik CA, Anzano MA, Sporn MB (1983) Transforming growth factors from neoplastic and nonneoplastic tissues. Fed Proc 42(9):2621–2626Google Scholar
  3. 3.
    Roberts AB, Anzano MA, Lamb LC, Smith JM, Sporn MB (1981) New class of transforming growth factors potentiated by epidermal growth factor: isolation from non-neoplastic tissues. Proc Natl Acad Sci USA 78(9):5339–5343Google Scholar
  4. 4.
    Anzano MA, Roberts AB, Smith JM, Sporn MB, De Larco JE (1983) Sarcoma growth factor from conditioned medium of virally transformed cells is composed of both type alpha and type beta transforming growth factors. Proc Natl Acad Sci USA 80(20):6264–6268Google Scholar
  5. 5.
    Roberts AB, Anzano MA, Meyers CA, Wideman J, Blacher R, Pan YC et al (1983) Purification and properties of a type beta transforming growth factor from bovine kidney. Biochemistry 22(25):5692–5698Google Scholar
  6. 6.
    Frolik CA, Dart LL, Meyers CA, Smith DM, Sporn MB (1983) Purification and initial characterization of a type beta transforming growth factor from human placenta. Proc Natl Acad Sci USA 80(12):3676–3680Google Scholar
  7. 7.
    Assoian RK, Komoriya A, Meyers CA, Miller DM, Sporn MB (1983) Transforming growth factor-beta in human platelets. Identification of a major storage site, purification, and characterization. J Biol Chem 258(11):7155–7160Google Scholar
  8. 8.
    Tucker RF, Volkenant ME, Branum EL, Moses HL (1983) Comparison of intra- and extracellular transforming growth factors from nontransformed and chemically transformed mouse embryo cells. Cancer Res 43(4):1581–1586Google Scholar
  9. 9.
    Nickell KA, Halper J, Moses HL (1983) Transforming growth factors in solid human malignant neoplasms. Cancer Res 43(5):1966–1971Google Scholar
  10. 10.
    Roberts AB, Anzano MA, Wakefield LM, Roche NS, Stern DF, Sporn MB (1985) Type beta transforming growth factor: a bifunctional regulator of cellular growth. Proc Natl Acad Sci USA 82(1):119–123Google Scholar
  11. 11.
    Shipley GD, Tucker RF, Moses HL (1985) Type beta transforming growth factor/growth inhibitor stimulates entry of monolayer cultures of AKR-2B cells into S phase after a prolonged prereplicative interval. Proc Natl Acad Sci USA 82(12):4147–4151Google Scholar
  12. 12.
    Tucker RF, Shipley GD, Moses HL, Holley RW (1984) Growth inhibitor from BSC-1 cells closely related to platelet type beta transforming growth factor. Science 226(4675):705–707Google Scholar
  13. 13.
    Roberts AB, Sporn MB (1990) The transforming growth factor beta. Springer, New York, NYGoogle Scholar
  14. 14.
    Roberts AB, Tian F, Byfield SD, Stuelten C, Ooshima A, Saika S et al (2006) Smad3 is key to TGF-beta-mediated epithelial-to-mesenchymal transition, fibrosis, tumor suppression and metastasis. Cytokine Growth Factor Rev 17(1–2):19–27Google Scholar
  15. 15.
    Massague J (2012) TGF-beta signaling in development and disease. FEBS Lett 586(14):1833Google Scholar
  16. 16.
    Roberts AB, Flanders KC, Heine UI, Jakowlew S, Kondaiah P, Kim SJ et al (1990) Transforming growth factor-beta: multifunctional regulator of differentiation and development. Philos Trans R Soc Lond B Biol Sci 327(1239):145–154Google Scholar
  17. 17.
    Jakowlew SB, Ciment G, Tuan RS, Sporn MB, Roberts AB (1992) Pattern of expression of transforming growth factor-beta 4 mRNA and protein in the developing chicken embryo. Dev Dyn 195(4):276–289Google Scholar
  18. 18.
    Kondaiah P, Sands MJ, Smith JM, Fields A, Roberts AB, Sporn MB et al (1990) Identification of a novel transforming growth factor-beta (TGF-beta 5) mRNA in Xenopus laevis. J Biol Chem 265(2):1089–1093Google Scholar
  19. 19.
    Sinha S, Nevett C, Shuttleworth CA, Kielty CM (1998) Cellular and extracellular biology of the latent transforming growth factor-beta binding proteins. Matrix Biol 17(8–9):529–545Google Scholar
  20. 20.
    Dubois CM, Laprise MH, Blanchette F, Gentry LE, Leduc R (1995) Processing of transforming growth factor beta 1 precursor by human furin convertase. J Biol Chem 270(18):10618–10624Google Scholar
  21. 21.
    Constam DB, Robertson EJ (1999) Regulation of bone morphogenetic protein activity by pro domains and proprotein convertases. J Cell Biol 144(1):139–149Google Scholar
  22. 22.
    Bailly S, Brand C, Chambaz EM, Feige JJ (1997) Analysis of small latent transforming growth factor-beta complex formation and dissociation by surface plasmon resonance. Absence of direct interaction with thrombospondins. J Biol Chem 272(26):16329–16334Google Scholar
  23. 23.
    Koli K, Saharinen J, Hyytiainen M, Penttinen C, Keski-Oja J (2001) Latency, activation, and binding proteins of TGF-beta. Microsc Res Tech 52(4):354–362Google Scholar
  24. 24.
    Keski-Oja J, Koli K, von Melchner H (2004) TGF-beta activation by traction? Trends Cell Biol 14(12):657–659Google Scholar
  25. 25.
    Lin HK, Yeh S, Kang HY, Chang C (2001) Akt suppresses androgen-induced apoptosis by phosphorylating and inhibiting androgen receptor. Proc Natl Acad Sci USA 98(13):7200–7205Google Scholar
  26. 26.
    Bizik J, Felnerova D, Grofova M, Vaheri A (1996) Active transforming growth factor-beta in human melanoma cell lines: no evidence for plasmin-related activation of latent TGF-beta. J Cell Biochem 62(1):113–122Google Scholar
  27. 27.
    Schultz-Cherry S, Ribeiro S, Gentry L, Murphy-Ullrich JE (1994) Thrombospondin binds and activates the small and large forms of latent transforming growth factor-beta in a chemically defined system. J Biol Chem 269(43):26775–26782Google Scholar
  28. 28.
    Shi M, Zhu J, Wang R, Chen X, Mi L, Walz T et al (2011) Latent TGF-beta structure and activation. Nature 474(7351):343–349Google Scholar
  29. 29.
    Dallas SL, Zhao S, Cramer SD, Chen Z, Peehl DM, Bonewald LF (2005) Preferential production of latent transforming growth factor beta-2 by primary prostatic epithelial cells and its activation by prostate-specific antigen. J Cell Physiol 202(2):361–370Google Scholar
  30. 30.
    Pasche B (2001) Role of transforming growth factor beta in cancer. J Cell Physiol 186(2):153–168Google Scholar
  31. 31.
    Massague J (1998) TGF-beta signal transduction. Annu Rev Biochem 67:753–791Google Scholar
  32. 32.
    Letterio JJ, Bottinger EP (1998) TGF-beta knockout and dominant-negative receptor transgenic mice. Miner Electrolyte Metab 24(2–3):161–167Google Scholar
  33. 33.
    Taya Y, O’Kane S, Ferguson MW (1999) Pathogenesis of cleft palate in TGF-beta3 knockout mice. Development 126(17):3869–3879Google Scholar
  34. 34.
    Dunker N, Krieglstein K (2002) Tgfbeta2 -/- Tgfbeta3 -/- double knockout mice display severe midline fusion defects and early embryonic lethality. Anat Embryol (Berl) 206(1–2):73–83Google Scholar
  35. 35.
    Roberts AB, Kim SJ, Noma T, Glick AB, Lafyatis R, Lechleider R et al (1991) Multiple forms of TGF-beta: distinct promoters and differential expression. Ciba Found Symp 157:7–15, discussion 15–28Google Scholar
  36. 36.
    Birchenall-Roberts MC, Ruscetti FW, Kasper J, Lee HD, Friedman R, Geiser A et al (1990) Transcriptional regulation of the transforming growth factor beta 1 promoter by v-src gene products is mediated through the AP-1 complex. Mol Cell Biol 10(9):4978–4983Google Scholar
  37. 37.
    Bang YJ, Kim SJ, Danielpour D, O’Reilly MA, Kim KY, Myers CE et al (1992) Cyclic AMP induces transforming growth factor beta 2 gene expression and growth arrest in the human androgen-independent prostate carcinoma cell line PC-3. Proc Natl Acad Sci USA 89(8):3556–3560Google Scholar
  38. 38.
    Geiser AG, Kim SJ, Roberts AB, Sporn MB (1991) Characterization of the mouse transforming growth factor-beta 1 promoter and activation by the Ha-ras oncogene. Mol Cell Biol 11(1):84–92Google Scholar
  39. 39.
    Glick AB, Flanders KC, Danielpour D, Yuspa SH, Sporn MB (1989) Retinoic acid induces transforming growth factor-beta 2 in cultured keratinocytes and mouse epidermis. Cell Regul 1(1):87–97Google Scholar
  40. 40.
    Glick AB, Danielpour D, Morgan D, Sporn MB, Yuspa SH (1990) Induction and autocrine receptor binding of transforming growth factor-beta 2 during terminal differentiation of primary mouse keratinocytes. Mol Endocrinol 4(1):46–52Google Scholar
  41. 41.
    Danielpour D (1996) Induction of transforming growth factor-beta autocrine activity by all-trans-­retinoic acid and 1 alpha,25-dihydroxyvitamin D3 in NRP-152 rat prostatic epithelial cells. J Cell Physiol 166(1):231–239Google Scholar
  42. 42.
    Danielpour D, Kim KY, Winokur TS, Sporn MB (1991) Differential regulation of the expression of transforming growth factor-beta s 1 and 2 by retinoic acid, epidermal growth factor, and dexamethasone in NRK-49 F and A549 cells. J Cell Physiol 148(2):235–244Google Scholar
  43. 43.
    Kim SJ, Angel P, Lafyatis R, Hattori K, Kim KY, Sporn MB et al (1990) Autoinduction of transforming growth factor beta 1 is mediated by the AP-1 complex. Mol Cell Biol 10(4):1492–1497Google Scholar
  44. 44.
    Kim SJ, Wagner S, Liu F, O’Reilly MA, Robbins PD, Green MR (1992) Retinoblastoma gene product activates expression of the human TGF-beta 2 gene through transcription factor ATF-­2. Nature 358(6384):331–334Google Scholar
  45. 45.
    Massague J (1985) Transforming growth factors. Isolation, characterization, and interaction with cellular receptors. Prog Med Virol 32:142–158Google Scholar
  46. 46.
    Wrana JL, Attisano L, Carcamo J, Zentella A, Doody J, Laiho M et al (1992) TGF beta signals through a heteromeric protein kinase receptor complex. Cell 71(6):1003–1014Google Scholar
  47. 47.
    Inagaki M, Moustakas A, Lin HY, Lodish HF, Carr BI (1993) Growth inhibition by transforming growth factor beta (TGF-beta) type I is restored in TGF-beta-resistant hepatoma cells after expression of TGF-beta receptor type II cDNA. Proc Natl Acad Sci USA 90(11):5359–5363Google Scholar
  48. 48.
    Wrana JL, Attisano L, Wieser R, Ventura F, Massague J (1994) Mechanism of activation of the TGF-beta receptor. Nature 370(6488):341–347Google Scholar
  49. 49.
    Attisano L, Wrana JL, Lopez-Casillas F, Massague J (1994) TGF-beta receptors and actions. Biochim Biophys Acta 1222(1):71–80Google Scholar
  50. 50.
    MacKay K, Danielpour D (1991) Novel 150- and 180-kDa glycoproteins that bind transforming growth factor (TGF)-beta 1 but not TGF-beta 2 are present in several cell lines. J Biol Chem 266(15):9907–9911Google Scholar
  51. 51.
    MacKay K, Danielpour D, Miller D, Border WA, Robbins AR (1992) The 260-kDa transforming growth factor (TGF)-beta binding protein in rat glomeruli is a complex comprised of 170- and 85-kDa TGF-beta binding proteins. J Biol Chem 267(16):11449–11454Google Scholar
  52. 52.
    MacKay K, Robbins AR, Bruce MD, Danielpour D (1990) Identification of disulfide-linked transforming growth factor-beta 1-specific binding proteins in rat glomeruli. J Biol Chem 265(16):9351–9356Google Scholar
  53. 53.
    Henis YI, Moustakas A, Lin HY, Lodish HF (1994) The types II and III transforming growth factor-beta receptors form homo-oligomers. J Cell Biol 126(1):139–154Google Scholar
  54. 54.
    Luo K, Lodish HF (1996) Signaling by chimeric erythropoietin-TGF-beta receptors: homodimerization of the cytoplasmic domain of the type I TGF-beta receptor and heterodimerization with the type II receptor are both required for intracellular signal transduction. EMBO J 15(17):4485–4496Google Scholar
  55. 55.
    Luo K, Lodish HF (1997) Positive and negative regulation of type II TGF-beta receptor signal transduction by autophosphorylation on multiple serine residues. EMBO J 16(8):1970–1981Google Scholar
  56. 56.
    Ebner R, Chen RH, Shum L, Lawler S, Zioncheck TF, Lee A et al (1993) Cloning of a type I TGF-beta receptor and its effect on TGF-beta binding to the type II receptor. Science 260(5112):1344–1348Google Scholar
  57. 57.
    Lin HY, Wang XF, Ng-Eaton E, Weinberg RA, Lodish HF (1992) Expression cloning of the TGF-beta type II receptor, a functional transmembrane serine/threonine kinase. Cell 68(4):775–785Google Scholar
  58. 58.
    Wang XF, Lin HY, Ng-Eaton E, Downward J, Lodish HF, Weinberg RA (1991) Expression cloning and characterization of the TGF-beta type III receptor. Cell 67(4):797–805Google Scholar
  59. 59.
    Lopez-Casillas F, Wrana JL, Massague J (1993) Betaglycan presents ligand to the TGF beta signaling receptor. Cell 73(7):1435–1444Google Scholar
  60. 60.
    Andres JL, Stanley K, Cheifetz S, Massague J (1989) Membrane-anchored and soluble forms of betaglycan, a polymorphic proteoglycan that binds transforming growth factor-beta. J Cell Biol 109(6 Pt 1):3137–3145Google Scholar
  61. 61.
    Charng MJ, Kinnunen P, Hawker J, Brand T, Schneider MD (1996) FKBP-12 recognition is dispensable for signal generation by type I transforming growth factor-beta receptors. J Biol Chem 271(38):22941–22944Google Scholar
  62. 62.
    Charng MJ, Zhang D, Kinnunen P, Schneider MD (1998) A novel protein distinguishes between quiescent and activated forms of the type I transforming growth factor beta receptor. J Biol Chem 273(16):9365–9368Google Scholar
  63. 63.
    Chen YG, Liu F, Massague J (1997) Mechanism of TGFbeta receptor inhibition by FKBP12. EMBO J 16(13):3866–3876Google Scholar
  64. 64.
    Hu JS, Olson EN (1988) Regulation of differentiation of the BC3H1 muscle cell line through cAMP-dependent and -independent pathways. J Biol Chem 263(36):19670–19677Google Scholar
  65. 65.
    Engel ME, Datta PK, Moses HL (1998) Signal transduction by transforming growth factor-­beta: a cooperative paradigm with extensive negative regulation. J Cell Biochem Suppl 31:111–122Google Scholar
  66. 66.
    Massague J (1996) TGFbeta signaling: receptors, transducers, and Mad proteins. Cell 85(7):947–950Google Scholar
  67. 67.
    Liu F, Pouponnot C, Massague J (1997) Dual role of the Smad4/DPC4 tumor suppressor in TGFbeta-inducible transcriptional complexes. Genes Dev 11(23):3157–3167Google Scholar
  68. 68.
    Wrana J, Pawson T (1997) Signal transduction. Mad about SMADs [news; comment]. Nature 388(6637):28–29Google Scholar
  69. 69.
    Kretzschmar M, Massague J (1998) SMADs: mediators and regulators of TGF-beta signaling. Curr Opin Genet Dev 8(1):103–111Google Scholar
  70. 70.
    Shi Y, Wang YF, Jayaraman L, Yang H, Massague J, Pavletich NP (1998) Crystal structure of a Smad MH1 domain bound to DNA: insights on DNA binding in TGF-beta signaling. Cell 94(5):585–594Google Scholar
  71. 71.
    Yagi K, Goto D, Hamamoto T, Takenoshita S, Kato M, Miyazono K (1999) Alternatively spliced variant of Smad2 lacking exon 3. Comparison with wild-type Smad2 and Smad3. J Biol Chem 274(2):703–709Google Scholar
  72. 72.
    Chen YG, Hata A, Lo RS, Wotton D, Shi Y, Pavletich N et al (1998) Determinants of specificity in TGF-beta signal transduction. Genes Dev 12(14):2144–2152Google Scholar
  73. 73.
    Feng XH, Derynck R (1997) A kinase subdomain of transforming growth factor-beta (TGF-­beta) type I receptor determines the TGF-beta intracellular signaling specificity. EMBO J 16(13):3912–3923Google Scholar
  74. 74.
    Lo RS, Chen YG, Shi Y, Pavletich NP, Massague J (1998) The L3 loop: a structural motif determining specific interactions between SMAD proteins and TGF-beta receptors. EMBO J 17(4):996–1005Google Scholar
  75. 75.
    Tsukazaki T, Chiang TA, Davison AF, Attisano L, Wrana JL (1998) SARA, a FYVE domain protein that recruits Smad2 to the TGFbeta receptor. Cell 95(6):779–791Google Scholar
  76. 76.
    Miura S, Takeshita T, Asao H, Kimura Y, Murata K, Sasaki Y et al (2000) Hgs (Hrs), a FYVE domain protein, is involved in Smad signaling through cooperation with SARA. Mol Cell Biol 20(24):9346–9355Google Scholar
  77. 77.
    Moskaluk CA, Hruban RH, Schutte M, Lietman AS, Smyrk T, Fusaro L et al (1997) Genomic sequencing of DPC4 in the analysis of familial pancreatic carcinoma. Diagn Mol Pathol 6(2):85–90Google Scholar
  78. 78.
    Wu RY, Zhang Y, Feng XH, Derynck R (1997) Heteromeric and homomeric interactions correlate with signaling activity and functional cooperativity of Smad3 and Smad4/DPC4. Mol Cell Biol 17(5):2521–2528Google Scholar
  79. 79.
    Xiao Z, Liu X, Lodish HF (2000) Importin beta mediates nuclear translocation of Smad 3. J Biol Chem 275(31):23425–23428Google Scholar
  80. 80.
    Dong C, Li Z, Alvarez R Jr, Feng XH, Goldschmidt-Clermont PJ (2000) Microtubule binding to Smads may regulate TGF beta activity. Mol Cell 5(1):27–34Google Scholar
  81. 81.
    Kurisaki A, Kose S, Yoneda Y, Heldin CH, Moustakas A (2001) Transforming growth factor-­beta induces nuclear import of Smad3 in an importin-beta1 and Ran-dependent manner. Mol Biol Cell 12(4):1079–1091Google Scholar
  82. 82.
    Matsuzaki K (2011) Smad phosphoisoform signaling specificity: the right place at the right time. Carcinogenesis 32(11):1578–1588Google Scholar
  83. 83.
    Ten Dijke P, Goumans MJ, Itoh F, Itoh S (2002) Regulation of cell proliferation by Smad proteins. J Cell Physiol 191(1):1–16Google Scholar
  84. 84.
    Liu X, Sun Y, Constantinescu SN, Karam E, Weinberg RA, Lodish HF (1997) Transforming growth factor beta-induced phosphorylation of Smad3 is required for growth inhibition and transcriptional induction in epithelial cells. Proc Natl Acad Sci USA 94(20):10669–10674Google Scholar
  85. 85.
    Yamamura Y, Hua X, Bergelson S, Lodish HF (2000) Critical role of smads and AP-1 complex in TGF-{beta}-dependent apoptosis. J Biol Chem 275(46):36295–36302Google Scholar
  86. 86.
    Jonk LJ, Itoh S, Heldin CH, ten Dijke P, Kruijer W (1998) Identification and functional characterization of a Smad binding element (SBE) in the JunB promoter that acts as a transforming growth factor-beta, activin, and bone morphogenetic protein-inducible enhancer. J Biol Chem 273(33):21145–21152Google Scholar
  87. 87.
    Piek E, Heldin CH, Ten Dijke P (1999) Specificity, diversity, and regulation in TGF-beta superfamily signaling. FASEB J 13(15):2105–2124Google Scholar
  88. 88.
    Wakefield LM, Roberts AB (2002) TGF-beta signaling: positive and negative effects on tumorigenesis. Curr Opin Genet Dev 12(1):22–29Google Scholar
  89. 89.
    Wendt MK, Tian M, Schiemann WP (2012) Deconstructing the mechanisms and consequences of TGF-beta-induced EMT during cancer progression. Cell Tissue Res 347(1):85–101Google Scholar
  90. 90.
    Inoue Y, Imamura T (2008) Regulation of TGF-beta family signaling by E3 ubiquitin ligases. Cancer Sci 99(11):2107–2112Google Scholar
  91. 91.
    Lin X, Duan X, Liang YY, Su Y, Wrighton KH, Long J et al (2006) PPM1A functions as a Smad phosphatase to terminate TGFbeta signaling. Cell 125(5):915–928Google Scholar
  92. 92.
    Wrana JL, Attisano L (2000) The Smad pathway. Cytokine Growth Factor Rev 11(1–2):5–13Google Scholar
  93. 93.
    Massague J (2000) How cells read TGF-beta signals. Nat Rev Mol Cell Biol 1(3):169–178Google Scholar
  94. 94.
    Robson CN, Gnanapragasam V, Byrne RL, Collins AT, Neal DE (1999) Transforming growth factor-beta1 up-regulates p15, p21 and p27 and blocks cell cycling in G1 in human prostate epithelium. J Endocrinol 160(2):257–266Google Scholar
  95. 95.
    Li JM, Nichols MA, Chandrasekharan S, Xiong Y, Wang XF (1995) Transforming growth factor beta activates the promoter of cyclin-dependent kinase inhibitor p15INK4B through an Sp1 consensus site. J Biol Chem 270(45):26750–26753Google Scholar
  96. 96.
    Iavarone A, Massague J (1999) E2F and histone deacetylase mediate transforming growth factor beta repression of cdc25A during keratinocyte cell cycle arrest. Mol Cell Biol 19(1):916–922Google Scholar
  97. 97.
    Seoane J, Pouponnot C, Staller P, Schader M, Eilers M, Massague J (2001) TGFbeta influences Myc, Miz-1 and Smad to control the CDK inhibitor p15INK4b. Nat Cell Biol 3(4):400–408Google Scholar
  98. 98.
    Staller P, Peukert K, Kiermaier A, Seoane J, Lukas J, Karsunky H et al (2001) Repression of p15INK4b expression by Myc through association with Miz-1. Nat Cell Biol 3(4):392–399Google Scholar
  99. 99.
    Yagi K, Furuhashi M, Aoki H, Goto D, Kuwano H, Sugamura K et al (2002) c-myc is a downstream target of the Smad pathway. J Biol Chem 277(1):854–861Google Scholar
  100. 100.
    Hung WC, Chang HC, Chuang LY (1998) Transforming growth factor beta 1 potently activates CPP32-like proteases in human hepatoma cells. Cell Signal 10(7):511–515Google Scholar
  101. 101.
    Shima Y, Nakao K, Nakashima T, Kawakami A, Nakata K, Hamasaki K et al (1999) Activation of caspase-8 in transforming growth factor-beta-induced apoptosis of human hepatoma cells. Hepatology 30(5):1215–1222Google Scholar
  102. 102.
    Schrantz N, Blanchard DA, Auffredou MT, Sharma S, Leca G, Vazquez A (1999) Role of caspases and possible involvement of retinoblastoma protein during TGFbeta-mediated apoptosis of human B lymphocytes. Oncogene 18(23):3511–3519Google Scholar
  103. 103.
    Brown TL, Patil S, Basnett RK, Howe PH (1998) Caspase inhibitor BD-fmk distinguishes transforming growth factor beta-induced apoptosis from growth inhibition. Cell Growth Differ 9(10):869–875Google Scholar
  104. 104.
    Brown TL, Patil S, Cianci CD, Morrow JS, Howe PH (1999) Transforming growth factor beta induces caspase 3-independent cleavage of alphaII-spectrin (alpha-fodrin) coincident with apoptosis. J Biol Chem 274(33):23256–23262Google Scholar
  105. 105.
    Chipuk JE, Bhat M, Hsing AY, Ma J, Danielpour D (2001) Bcl-xL blocks transforming growth factor-beta 1-induced apoptosis by inhibiting cytochrome c release and not by directly antagonizing Apaf-1-dependent caspase activation in prostate epithelial cells. J Biol Chem 276(28):26614–26621Google Scholar
  106. 106.
    Ahmed MM, Alcock RA, Chendil D, Dey S, Das A, Venkatasubbarao K et al (2002) Restoration of transforming growth factor-beta signaling enhances radiosensitivity by altering the Bcl-2/Bax ratio in the p53 mutant pancreatic cancer cell line MIA PaCa-2. J Biol Chem 277(3):2234–2246Google Scholar
  107. 107.
    Jang CW, Chen CH, Chen CC, Chen JY, Su YH, Chen RH (2002) TGF-beta induces apoptosis through Smad-mediated expression of DAP-kinase. Nat Cell Biol 4(1):51–58Google Scholar
  108. 108.
    Yamaguchi K, Nagai S, Ninomiya-Tsuji J, Nishita M, Tamai K, Irie K et al (1999) XIAP, a cellular member of the inhibitor of apoptosis protein family, links the receptors to TAB1-­TAK1 in the BMP signaling pathway. EMBO J 18(1):179–187Google Scholar
  109. 109.
    Perlman R, Schiemann WP, Brooks MW, Lodish HF, Weinberg RA (2001) TGF-beta-induced apoptosis is mediated by the adapter protein Daxx that facilitates JNK activation. Nat Cell Biol 3(8):708–714Google Scholar
  110. 110.
    Saile B, Matthes N, El Armouche H, Neubauer K, Ramadori G (2001) The bcl, NFkappaB and p53/p21WAF1 systems are involved in spontaneous apoptosis and in the anti-apoptotic effect of TGF-beta or TNF-alpha on activated hepatic stellate cells. Eur J Cell Biol 80(8):554–561Google Scholar
  111. 111.
    Edlund S, Bu S, Schuster N, Aspenstrom P, Heuchel R, Heldin NE et al (2003) Transforming growth factor-beta1 (TGF-beta)-induced apoptosis of prostate cancer cells involves Smad7-­dependent activation of p38 by TGF-beta-activated kinase 1 and mitogen-activated protein kinase kinase 3. Mol Biol Cell 14(2):529–544Google Scholar
  112. 112.
    Valluru M, Staton CA, Reed MW, Brown NJ (2011) Transforming growth factor-beta and endoglin signaling orchestrate wound healing. Front Physiol 2:89Google Scholar
  113. 113.
    Roberts AB, McCune BK, Sporn MB (1992) TGF-beta: regulation of extracellular matrix. Kidney Int 41(3):557–559Google Scholar
  114. 114.
    Prud’homme GJ, Piccirillo CA (2000) The inhibitory effects of transforming growth factor-beta-­1 (TGF-beta1) in autoimmune diseases. J Autoimmun 14(1):23–42Google Scholar
  115. 115.
    Crowe MJ, Doetschman T, Greenhalgh DG (2000) Delayed wound healing in immunodeficient TGF-beta 1 knockout mice. J Invest Dermatol 115(1):3–11Google Scholar
  116. 116.
    Ashcroft GS, Yang X, Glick AB, Weinstein M, Letterio JL, Mizel DE et al (1999) Mice lacking Smad3 show accelerated wound healing and an impaired local inflammatory response. Nat Cell Biol 1(5):260–266Google Scholar
  117. 117.
    Zheng X, Wang J, Haerry TE, Wu AY, Martin J, O’Connor MB et al (2003) TGF-beta signaling activates steroid hormone receptor expression during neuronal remodeling in the Drosophila brain. Cell 112(3):303–315Google Scholar
  118. 118.
    Kyprianou N, Isaacs JT (1988) Identification of a cellular receptor for transforming growth factor-beta in rat ventral prostate and its negative regulation by androgens. Endocrinology 123(4):2124–2131Google Scholar
  119. 119.
    Wikstrom P, Bergh A, Damber JE (1997) Expression of transforming growth factor-beta receptor type I and type II in rat ventral prostate and Dunning R3327 PAP adenocarcinoma in response to castration and oestrogen treatment. Urol Res 25(2):103–111Google Scholar
  120. 120.
    Brodin G, ten Dijke P, Funa K, Heldin CH, Landstrom M (1999) Increased smad expression and activation are associated with apoptosis in normal and malignant prostate after castration. Cancer Res 59(11):2731–2738Google Scholar
  121. 121.
    Kundu SD, Kim IY, Yang T, Doglio L, Lang S, Zhang X et al (2000) Absence of proximal duct apoptosis in the ventral prostate of transgenic mice carrying the C3(1)-TGF-beta type II dominant negative receptor. Prostate 43(2):118–124Google Scholar
  122. 122.
    Martikainen P, Kyprianou N, Isaacs JT (1990) Effect of transforming growth factor-beta 1 on proliferation and death of rat prostatic cells. Endocrinology 127(6):2963–2968Google Scholar
  123. 123.
    Peehl DM, Sellers RG (1997) Induction of smooth muscle cell phenotype in cultured human prostatic stromal cells. Exp Cell Res 232(2):208–215Google Scholar
  124. 124.
    Bhowmick NA, Chytil A, Plieth D, Gorska AE, Dumont N, Shappell S et al (2004) TGF-beta signaling in fibroblasts modulates the oncogenic potential of adjacent epithelia. Science 303(5659):848–851Google Scholar
  125. 125.
    Danielpour D (1999) Transdifferentiation of NRP-152 rat prostatic basal epithelial cells toward a luminal phenotype: regulation by glucocorticoid, insulin-like growth factor-I and transforming growth factor-beta. J Cell Sci 112(Pt 2):169–179Google Scholar
  126. 126.
    Salm SN, Koikawa Y, Ogilvie V, Tsujimura A, Coetzee S, Moscatelli D et al (2000) Generation of active TGF-beta by prostatic cell cocultures using novel basal and luminal prostatic epithelial cell lines. J Cell Physiol 184(1):70–79Google Scholar
  127. 127.
    Kyprianou N, Isaacs JT (1988) Activation of programmed cell death in the rat ventral prostate after castration. Endocrinology 122(2):552–562Google Scholar
  128. 128.
    Knudsen KE, Penning TM (2010) Partners in crime: deregulation of AR activity and androgen synthesis in prostate cancer. Trends Endocrinol Metab 21(5):315–324Google Scholar
  129. 129.
    Nishi N, Oya H, Matsumoto K, Nakamura T, Miyanaka H, Wada F (1996) Changes in gene expression of growth factors and their receptors during castration-induced involution and androgen-induced regrowth of rat prostates. Prostate 28(3):139–152Google Scholar
  130. 130.
    Fuzio P, Ditonno P, Rutigliano M, Battaglia M, Bettocchi C, Loverre A et al (2012) Regulation of TGF-beta1 expression by androgen deprivation therapy of prostate cancer. Cancer Lett 318(2):135–144Google Scholar
  131. 131.
    Hsing AY, Kadomatsu K, Bonham MJ, Danielpour D (1996) Regulation of apoptosis induced by transforming growth factor-beta1 in nontumorigenic rat prostatic epithelial cell lines. Cancer Res 56(22):5146–5149Google Scholar
  132. 132.
    Guo Y, Kyprianou N (1998) Overexpression of transforming growth factor (TGF) beta1 type II receptor restores TGF-beta1 sensitivity and signaling in human prostate cancer cells. Cell Growth Differ 9(2):185–193Google Scholar
  133. 133.
    Lucia MS, Sporn MB, Roberts AB, Stewart LV, Danielpour D (1998) The role of transforming growth factor-beta1, -beta2, and -beta3 in androgen-responsive growth of NRP-152 rat prostatic epithelial cells. J Cell Physiol 175(2):184–192Google Scholar
  134. 134.
    Chipuk JE, Cornelius SC, Pultz NJ, Jorgensen JS, Bonham MJ, Kim SJ et al (2002) The androgen receptor represses transforming growth factor-beta signaling through interaction with Smad3. J Biol Chem 277(2):1240–1248Google Scholar
  135. 135.
    Hayes SA, Zarnegar M, Sharma M, Yang F, Peehl DM, ten Dijke P et al (2001) SMAD3 represses androgen receptor-mediated transcription. Cancer Res 61(5):2112–2118Google Scholar
  136. 136.
    Kang HY, Huang KE, Chang SY, Ma WL, Lin WJ, Chang C (2002) Differential modulation of androgen receptor-mediated transactivation by Smad3 and tumor suppressor Smad4. J Biol Chem 277(46):43749–43756Google Scholar
  137. 137.
    Kang HY, Lin HK, Hu YC, Yeh S, Huang KE, Chang C (2001) From transforming growth factor-beta signaling to androgen action: identification of Smad3 as an androgen receptor coregulator in prostate cancer cells. Proc Natl Acad Sci USA 98(6):3018–3023Google Scholar
  138. 138.
    Hofmann TG, Stollberg N, Schmitz ML, Will H (2003) HIPK2 regulates transforming growth factor-beta-induced c-Jun NH(2)-terminal kinase activation and apoptosis in human hepatoma cells. Cancer Res 63(23):8271–8277Google Scholar
  139. 139.
    Song K, Wang H, Krebs TL, Wang B, Kelley TJ, Danielpour D (2010) DHT selectively reverses Smad3-mediated/TGF-beta-induced responses through transcriptional down-­regulation of Smad3 in prostate epithelial cells. Mol Endocrinol 24(10):2019–2029Google Scholar
  140. 140.
    Song K, Wang H, Krebs TL, Kim SJ, Danielpour D (2008) Androgenic control of transforming growth factor-beta signaling in prostate epithelial cells through transcriptional suppression of transforming growth factor-beta receptor II. Cancer Res 68(19):8173–8182Google Scholar
  141. 141.
    Kyprianou N (1999) Activation of TGF-beta signalling in human prostate cancer cells suppresses tumorigenicity via deregulation of cell cycle progression and induction of caspase-1 mediated apoptosis: significance in prostate tumorigenesis. Prostate Cancer Prostatic Dis 2(S3):S18Google Scholar
  142. 142.
    Bruckheimer EM, Kyprianou N (2001) Dihydrotestosterone enhances transforming growth factor-beta-induced apoptosis in hormone-sensitive prostate cancer cells. Endocrinology 142(6):2419–2426Google Scholar
  143. 143.
    Bruckheimer EM, Kyprianou N (2002) Bcl-2 antagonizes the combined apoptotic effect of transforming growth factor-beta and dihydrotestosterone in prostate cancer cells. Prostate 53(2):133–142Google Scholar
  144. 144.
    Song K, Krebs TL, Danielpour D (2006) Novel permissive role of epidermal growth factor in transforming growth factor beta (TGF-beta) signaling and growth suppression. Mediation by stabilization of TGF-beta receptor type II. J Biol Chem 281(12):7765–7774Google Scholar
  145. 145.
    Carey JL, Sasur LM, Kawakubo H, Gupta V, Christian B, Bailey PM et al (2004) Mutually antagonistic effects of androgen and activin in the regulation of prostate cancer cell growth. Mol Endocrinol 18(3):696–707Google Scholar
  146. 146.
    Danielpour D, Kadomatsu K, Anzano MA, Smith JM, Sporn MB (1994) Development and characterization of nontumorigenic and tumorigenic epithelial cell lines from rat dorsal-­lateral prostate. Cancer Res 54(13):3413–3421Google Scholar
  147. 147.
    Yang J, Song K, Krebs TL, Jackson MW, Danielpour D (2008) Rb/E2F4 and Smad2/3 link survivin to TGF-beta-induced apoptosis and tumor progression. Oncogene 27(40):5326–5338Google Scholar
  148. 148.
    Yang J, Wahdan-Alaswad R, Danielpour D (2009) Critical role of Smad2 in tumor suppression and transforming growth factor-beta-induced apoptosis of prostate epithelial cells. Cancer Res 69(6):2185–2190Google Scholar
  149. 149.
    Kishi H, Igawa M, Kikuno N, Yoshino T, Urakami S, Shiina H (2004) Expression of the survivin gene in prostate cancer: correlation with clinicopathological characteristics, proliferative activity and apoptosis. J Urol 171(5):1855–1860Google Scholar
  150. 150.
    Zhang M, Latham DE, Delaney MA, Chakravarti A (2005) Survivin mediates resistance to antiandrogen therapy in prostate cancer. Oncogene 24(15):2474–2482Google Scholar
  151. 151.
    Altieri DC (2012) Targeting survivin in cancer. Cancer Lett [Epub ahead of print]Google Scholar
  152. 152.
    Nastiuk KL, Yoo K, Lo K, Su K, Yeung P, Kutaka J et al (2008) FLICE-like inhibitory protein blocks transforming growth factor beta 1-induced caspase activation and apoptosis in prostate epithelial cells. Mol Cancer Res 6(2):231–242Google Scholar
  153. 153.
    Yoo KS, Nastiuk KL, Krolewski JJ (2009) Transforming growth factor beta1 induces apoptosis by suppressing FLICE-like inhibitory protein in DU145 prostate epithelial cells. Int J Cancer 124(4):834–842Google Scholar
  154. 154.
    Perry KT, Anthony CT, Steiner MS (1997) Immunohistochemical localization of TGF beta 1, TGF beta 2, and TGF beta 3 in normal and malignant human prostate. Prostate 33(2):133–140Google Scholar
  155. 155.
    Guo Y, Jacobs SC, Kyprianou N (1997) Down-regulation of protein and mRNA expression for transforming growth factor-beta (TGF-beta1) type I and type II receptors in human prostate cancer. Int J Cancer 71(4):573–579Google Scholar
  156. 156.
    Kim IY, Ahn HJ, Zelner DJ, Shaw JW, Lang S, Kato M et al (1996) Loss of expression of transforming growth factor beta type I and type II receptors correlates with tumor grade in human prostate cancer tissues. Clin Cancer Res 2(8):1255–1261Google Scholar
  157. 157.
    Kim IY, Ahn HJ, Zelner DJ, Shaw JW, Sensibar JA, Kim JH et al (1996) Genetic change in transforming growth factor beta (TGF-beta) receptor type I gene correlates with insensitivity to TGF-beta 1 in human prostate cancer cells. Cancer Res 56(1):44–48Google Scholar
  158. 158.
    Williams RH, Stapleton AM, Yang G, Truong LD, Rogers E, Timme TL et al (1996) Reduced levels of transforming growth factor beta receptor type II in human prostate cancer: an immunohistochemical study. Clin Cancer Res 2(4):635–640Google Scholar
  159. 159.
    Sharifi N, Hurt EM, Kawasaki BT, Farrar WL (2007) TGFBR3 loss and consequences in prostate cancer. Prostate 67(3):301–311Google Scholar
  160. 160.
    Turley RS, Finger EC, Hempel N, How T, Fields TA, Blobe GC (2007) The type III transforming growth factor-beta receptor as a novel tumor suppressor gene in prostate cancer. Cancer Res 67(3):1090–1098Google Scholar
  161. 161.
    Ajiboye S, Sissung TM, Sharifi N, Fig. WD (2010) More than an accessory: implications of type III transforming growth factor-beta receptor loss in prostate cancer. BJU Int 105(7):913–916Google Scholar
  162. 162.
    Guo Y, Kyprianou N (1999) Restoration of transforming growth factor beta signaling pathway in human prostate cancer cells suppresses tumorigenicity via induction of caspase-1-­mediated apoptosis. Cancer Res 59(6):1366–1371Google Scholar
  163. 163.
    Hayward SW, Haughney PC, Lopes ES, Danielpour D, Cunha GR (1999) The rat prostatic epithelial cell line NRP-152 can differentiate in vivo in response to its stromal environment. Prostate 39(3):205–212Google Scholar
  164. 164.
    Song K, Cornelius SC, Danielpour D (2003) Development and characterization of DP-153, a nontumorigenic prostatic cell line that undergoes malignant transformation by expression of dominant-negative transforming growth factor beta receptor type II. Cancer Res 63(15):4358–4367Google Scholar
  165. 165.
    Tu WH, Thomas TZ, Masumori N, Bhowmick NA, Gorska AE, Shyr Y et al (2003) The loss of TGF-beta signaling promotes prostate cancer metastasis. Neoplasia 5(3):267–277Google Scholar
  166. 166.
    Pu H, Collazo J, Jones E, Gayheart D, Sakamoto S, Vogt A et al (2009) Dysfunctional transforming growth factor-beta receptor II accelerates prostate tumorigenesis in the TRAMP mouse model. Cancer Res 69(18):7366–7374Google Scholar
  167. 167.
    Markowitz S, Wang J, Myeroff L, Parsons R, Sun L, Lutterbaugh J et al (1995) Inactivation of the type II TGF-beta receptor in colon cancer cells with microsatellite instability [see comments]. Science 268(5215):1336–1338Google Scholar
  168. 168.
    Massague J (2008) TGFbeta in cancer. Cell 134(2):215–230Google Scholar
  169. 169.
    Huggins C, Hodges CV (1972) Studies on prostatic cancer. I. The effect of castration, of estrogen and androgen injection on serum phosphatases in metastatic carcinoma of the prostate. CA Cancer J Clin 22(4):232–240Google Scholar
  170. 170.
    Kuiper GG, Brinkmann AO (1995) Phosphotryptic peptide analysis of the human androgen receptor: detection of a hormone-induced phosphopeptide. Biochemistry 34(6):1851–1857Google Scholar
  171. 171.
    Hsiao PW, Lin DL, Nakao R, Chang C (1999) The linkage of Kennedy’s neuron disease to ARA24, the first identified androgen receptor polyglutamine region-associated coactivator. J Biol Chem 274(29):20229–20234Google Scholar
  172. 172.
    Hsiao PW, Chang C (1999) Isolation and characterization of ARA160 as the first androgen receptor N-terminal-associated coactivator in human prostate cells. J Biol Chem 274(32):22373–22379Google Scholar
  173. 173.
    Fujimoto N, Yeh S, Kang HY, Inui S, Chang HC, Mizokami A et al (1999) Cloning and characterization of androgen receptor coactivator, ARA55, in human prostate. J Biol Chem 274(12):8316–8321Google Scholar
  174. 174.
    Kang HY, Yeh S, Fujimoto N, Chang C (1999) Cloning and characterization of human prostate coactivator ARA54, a novel protein that associates with the androgen receptor. J Biol Chem 274(13):8570–8576Google Scholar
  175. 175.
    Wang X, Yeh S, Wu G, Hsu CL, Wang L, Chiang T et al (2001) Identification and characterization of a novel androgen receptor coregulator ARA267-alpha in prostate cancer cells. J Biol Chem 276(44):40417–40423Google Scholar
  176. 176.
    Yeh S, Sampson ER, Lee DK, Kim E, Hsu CL, Chen YL et al (2000) Functional analysis of androgen receptor N-terminal and ligand binding domain interacting coregulators in prostate cancer. J Formos Med Assoc 99(12):885–894Google Scholar
  177. 177.
    Fronsdal K, Engedal N, Slagsvold T, Saatcioglu F (1998) CREB binding protein is a coactivator for the androgen receptor and mediates cross-talk with AP-1. J Biol Chem 273(48):31853–31859Google Scholar
  178. 178.
    Ikonen T, Palvimo JJ, Janne OA (1997) Interaction between the amino- and carboxyl-­terminal regions of the rat androgen receptor modulates transcriptional activity and is influenced by nuclear receptor coactivators. J Biol Chem 272(47):29821–29828Google Scholar
  179. 179.
    Schneikert J, Peterziel H, Defossez PA, Klocker H, Launoit Y, Cato AC (1996) Androgen receptor-Ets protein interaction is a novel mechanism for steroid hormone-mediated down-­modulation of matrix metalloproteinase expression. J Biol Chem 271(39):23907–23913Google Scholar
  180. 180.
    Hong H, Kohli K, Garabedian MJ, Stallcup MR (1997) GRIP1, a transcriptional coactivator for the AF-2 transactivation domain of steroid, thyroid, retinoid, and vitamin D receptors. Mol Cell Biol 17(5):2735–2744Google Scholar
  181. 181.
    Bubulya A, Wise SC, Shen XQ, Burmeister LA, Shemshedini L (1996) c-Jun can mediate androgen receptor-induced transactivation. J Biol Chem 271(40):24583–24589Google Scholar
  182. 182.
    Qiu T, Grizzle WE, Oelschlager DK, Shen X, Cao X (2007) Control of prostate cell growth: BMP antagonizes androgen mitogenic activity with incorporation of MAPK signals in Smad1. EMBO J 26(2):346–357Google Scholar
  183. 183.
    Wahdan-Alaswad RS, Bane KL, Song K, Shola DT, Garcia JA, Danielpour D (2012) Inhibition of mTORC1 kinase activates Smads 1 and 5 but not Smad8 in human prostate cancer cells, mediating cytostatic response to rapamycin. Mol Cancer Res 10(6):821–833Google Scholar
  184. 184.
    Song K, Wang H, Krebs TL, Danielpour D (2006) Novel roles of Akt and mTOR in suppressing TGF-beta/ALK5-mediated Smad3 activation. EMBO J 25(1):58–69Google Scholar
  185. 185.
    van der Poel HG (2005) Androgen receptor and TGFbeta1/Smad signaling are mutually inhibitory in prostate cancer. Eur Urol 48(6):1051–1058Google Scholar
  186. 186.
    Ashcroft GS, Mills SJ, Flanders KC, Lyakh LA, Anzano MA, Gilliver SC et al (2003) Role of Smad3 in the hormonal modulation of in vivo wound healing responses. Wound Repair Regen 11(6):468–473Google Scholar
  187. 187.
    Morgan TM, Koreckij TD, Corey E (2009) Targeted therapy for advanced prostate cancer: inhibition of the PI3K/Akt/mTOR pathway. Curr Cancer Drug Targets 9(2):237–249Google Scholar
  188. 188.
    Laplante M, Sabatini DM (2012) mTOR signaling in growth control and disease. Cell 149(2):274–293Google Scholar
  189. 189.
    Kaplan PJ, Mohan S, Cohen P, Foster BA, Greenberg NM (1999) The insulin-like growth factor axis and prostate cancer: lessons from the transgenic adenocarcinoma of mouse prostate (TRAMP) model. Cancer Res 59(9):2203–2209Google Scholar
  190. 190.
    Giovannucci E (1999) Insulin-like growth factor-I and binding protein-3 and risk of cancer. Horm Res 51(Suppl 3):34–41Google Scholar
  191. 191.
    Nickerson T, Pollak M, Huynh H (1998) Castration-induced apoptosis in the rat ventral prostate is associated with increased expression of genes encoding insulin-like growth factor binding proteins 2,3,4 and 5. Endocrinology 139(2):807–810Google Scholar
  192. 192.
    Culig Z, Hobisch A, Cronauer MV, Radmayr C, Trapman J, Hittmair A et al (1994) Androgen receptor activation in prostatic tumor cell lines by insulin-like growth factor-I, keratinocyte growth factor, and epidermal growth factor. Cancer Res 54(20):5474–5478Google Scholar
  193. 193.
    Danielpour D, Song K (2006) Cross-talk between IGF-I and TGF-beta signaling pathways. Cytokine Growth Factor Rev 17(1–2):59–74Google Scholar
  194. 194.
    Chan JM, Stampfer MJ, Giovannucci E, Gann PH, Ma J, Wilkinson P et al (1998) Plasma insulin-like growth factor-I and prostate cancer risk: a prospective study. Science 279(5350):563–566Google Scholar
  195. 195.
    Stattin P, Bylund A, Rinaldi S, Biessy C, Dechaud H, Stenman UH et al (2000) Plasma insulin-like growth factor-I, insulin-like growth factor-binding proteins, and prostate cancer risk: a prospective study. J Natl Cancer Inst 92(23):1910–1917Google Scholar
  196. 196.
    DiGiovanni J, Kiguchi K, Frijhoff A, Wilker E, Bol DK, Beltran L et al (2000) Deregulated expression of insulin-like growth factor 1 in prostate epithelium leads to neoplasia in transgenic mice. Proc Natl Acad Sci USA 97(7):3455–3460Google Scholar
  197. 197.
    Baserga R, Morrione A (1999) Differentiation and malignant transformation: two roads diverged in a wood. J Cell Biochem Suppl 32–33:68–75Google Scholar
  198. 198.
    Baserga R, Hongo A, Rubini M, Prisco M, Valentinis B (1997) The IGF-I receptor in cell growth, transformation and apoptosis. Biochim Biophys Acta 1332(3):F105–F126Google Scholar
  199. 199.
    Baserga R (1999) The IGF-I receptor in cancer research. Exp Cell Res 253(1):1–6Google Scholar
  200. 200.
    Baserga R (1995) The insulin-like growth factor I receptor: a key to tumor growth? Cancer Res 55(2):249–252Google Scholar
  201. 201.
    Nicholson KM, Anderson NG (2002) The protein kinase B/Akt signalling pathway in human malignancy. Cell Signal 14(5):381–395Google Scholar
  202. 202.
    Wu X, Senechal K, Neshat MS, Whang YE, Sawyers CL (1998) The PTEN/MMAC1 tumor suppressor phosphatase functions as a negative regulator of the phosphoinositide 3-kinase/Akt pathway. Proc Natl Acad Sci USA 95(26):15587–15591Google Scholar
  203. 203.
    Wen Y, Hu MC, Makino K, Spohn B, Bartholomeusz G, Yan DH et al (2000) HER-2/neu promotes androgen-independent survival and growth of prostate cancer cells through the Akt pathway. Cancer Res 60(24):6841–6845Google Scholar
  204. 204.
    Sharma M, Chuang WW, Sun Z (2002) Phosphatidylinositol 3-kinase/Akt stimulates androgen pathway through GSK3beta inhibition and nuclear beta-catenin accumulation. J Biol Chem 277(34):30935–30941Google Scholar
  205. 205.
    Graff JR, Konicek BW, McNulty AM, Wang Z, Houck K, Allen S et al (2000) Increased AKT activity contributes to prostate cancer progression by dramatically accelerating prostate tumor growth and diminishing p27Kip1 expression. J Biol Chem 275(32):24500–24505Google Scholar
  206. 206.
    Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI et al (1997) PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 275(5308):1943–1947Google Scholar
  207. 207.
    Cairns P, Okami K, Halachmi S, Halachmi N, Esteller M, Herman JG et al (1997) Frequent inactivation of PTEN/MMAC1 in primary prostate cancer. Cancer Res 57(22):4997–5000Google Scholar
  208. 208.
    Suzuki H, Freije D, Nusskern DR, Okami K, Cairns P, Sidransky D et al (1998) Interfocal heterogeneity of PTEN/MMAC1 gene alterations in multiple metastatic prostate cancer tissues. Cancer Res 58(2):204–209Google Scholar
  209. 209.
    Whang YE, Wu X, Suzuki H, Reiter RE, Tran C, Vessella RL et al (1998) Inactivation of the tumor suppressor PTEN/MMAC1 in advanced human prostate cancer through loss of expression. Proc Natl Acad Sci USA 95(9):5246–5250Google Scholar
  210. 210.
    Vlietstra RJ, van Alewijk DC, Hermans KG, van Steenbrugge GJ, Trapman J (1998) Frequent inactivation of PTEN in prostate cancer cell lines and xenografts. Cancer Res 58(13):2720–2723Google Scholar
  211. 211.
    Facher EA, Law JC (1998) PTEN and prostate cancer. J Med Genet 35(9):790Google Scholar
  212. 212.
    Stambolic V, Suzuki A, de la Pompa JL, Brothers GM, Mirtsos C, Sasaki T et al (1998) Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN. Cell 95(1):29–39Google Scholar
  213. 213.
    Blume-Jensen P, Hunter T (2001) Oncogenic kinase signalling. Nature 411(6835):355–365Google Scholar
  214. 214.
    Song K, Cornelius SC, Reiss M, Danielpour D (2003) Insulin-like growth factor-I inhibits transcriptional responses of transforming growth factor-beta by phosphatidylinositol 3-kinase/Akt-dependent suppression of the activation of Smad3 but not Smad2. J Biol Chem 278(40):38342–38351Google Scholar
  215. 215.
    Huse M, Muir TW, Xu L, Chen YG, Kuriyan J, Massague J (2001) The TGF beta receptor activation process: an inhibitor- to substrate-binding switch. Mol Cell 8(3):671–682Google Scholar
  216. 216.
    Law BK, Chytil A, Dumont N, Hamilton EG, Waltner-Law ME, Aakre ME et al (2002) Rapamycin potentiates transforming growth factor beta-induced growth arrest in nontransformed, oncogene-transformed, and human cancer cells. Mol Cell Biol 22(23):8184–8198Google Scholar
  217. 217.
    Remy I, Montmarquette A, Michnick SW (2004) PKB/Akt modulates TGF-beta signalling through a direct interaction with Smad3. Nat Cell Biol 6(4):358–365Google Scholar
  218. 218.
    Lu TL, Chang JL, Liang CC, You LR, Chen CM (2007) Tumor spectrum, tumor latency and tumor incidence of the Pten-deficient mice. PLoS One 2(11):e1237Google Scholar
  219. 219.
    Ding Z, Wu CJ, Chu GC, Xiao Y, Ho D, Zhang J et al (2011) SMAD4-dependent barrier constrains prostate cancer growth and metastatic progression. Nature 470(7333):269–273Google Scholar
  220. 220.
    Zhang Q, Rubenstein JN, Jang TL, Pins M, Javonovic B, Yang X et al (2005) Insensitivity to transforming growth factor-beta results from promoter methylation of cognate receptors in human prostate cancer cells (LNCaP). Mol Endocrinol 19(9):2390–2399Google Scholar
  221. 221.
    Noda D, Itoh S, Watanabe Y, Inamitsu M, Dennler S, Itoh F et al (2006) ELAC2, a putative prostate cancer susceptibility gene product, potentiates TGF-beta/Smad-induced growth arrest of prostate cells. Oncogene 25(41):5591–5600Google Scholar
  222. 222.
    Trotman LC, Alimonti A, Scaglioni PP, Koutcher JA, Cordon-Cardo C, Pandolfi PP (2006) Identification of a tumour suppressor network opposing nuclear Akt function. Nature 441(7092):523–527Google Scholar
  223. 223.
    Lin HK, Bergmann S, Pandolfi PP (2004) Cytoplasmic PML function in TGF-beta signalling. Nature 431(7005):205–211Google Scholar
  224. 224.
    Xu W, Angelis K, Danielpour D, Haddad MM, Bischof O, Campisi J et al (2000) Ski acts as a co-repressor with Smad2 and Smad3 to regulate the response to type beta transforming growth factor. Proc Natl Acad Sci USA 97(11):5924–5929Google Scholar
  225. 225.
    Vo BT, Cody B, Cao Y, Khan SA (2012) Differential role of Sloan-Kettering Institute (Ski) protein in Nodal and transforming growth factor-beta (TGF-beta)-induced Smad signaling in prostate cancer cells. Carcinogenesis 33(11):2054–2064Google Scholar
  226. 226.
    Yang L, Pang Y, Moses HL (2010) TGF-beta and immune cells: an important regulatory axis in the tumor microenvironment and progression. Trends Immunol 31(6):220–227Google Scholar
  227. 227.
    Zhang Q, Yang X, Pins M, Javonovic B, Kuzel T, Kim SJ et al (2005) Adoptive transfer of tumor-reactive transforming growth factor-beta-insensitive CD8+ T cells: eradication of autologous mouse prostate cancer. Cancer Res 65(5):1761–1769Google Scholar
  228. 228.
    Zhang Q, Jang TL, Yang X, Park I, Meyer RE, Kundu S et al (2006) Infiltration of tumor-­reactive transforming growth factor-beta insensitive CD8+ T cells into the tumor parenchyma is associated with apoptosis and rejection of tumor cells. Prostate 66(3):235–247Google Scholar
  229. 229.
    Wang FL, Qin WJ, Wen WH, Tian F, Song B, Zhang Q et al (2007) TGF-beta insensitive dendritic cells: an efficient vaccine for murine prostate cancer. Cancer Immunol Immunother 56(11):1785–1793Google Scholar
  230. 230.
    Zhang F, Lee J, Lu S, Pettaway CA, Dong Z (2005) Blockade of transforming growth factor-­beta signaling suppresses progression of androgen-independent human prostate cancer in nude mice. Clin Cancer Res 11(12):4512–4520Google Scholar
  231. 231.
    Ao M, Williams K, Bhowmick NA, Hayward SW (2006) Transforming growth factor-beta promotes invasion in tumorigenic but not in nontumorigenic human prostatic epithelial cells. Cancer Res 66(16):8007–8016Google Scholar
  232. 232.
    Ao M, Franco OE, Park D, Raman D, Williams K, Hayward SW (2007) Cross-talk between paracrine-acting cytokine and chemokine pathways promotes malignancy in benign human prostatic epithelium. Cancer Res 67(9):4244–4253Google Scholar
  233. 233.
    Liu YN, Abou-Kheir W, Yin JJ, Fang L, Hynes P, Casey O et al (2012) Critical and reciprocal regulation of KLF4 and SLUG in transforming growth factor beta-initiated prostate cancer epithelial-mesenchymal transition. Mol Cell Biol 32(5):941–953Google Scholar
  234. 234.
    Matsuura I, Chiang KN, Lai CY, He D, Wang G, Ramkumar R et al (2010) Pin1 promotes transforming growth factor-beta-induced migration and invasion. J Biol Chem 285(3):1754–1764Google Scholar
  235. 235.
    Lim JH, Liu Y, Reineke E, Kao HY (2011) Mitogen-activated protein kinase extracellular signal-regulated kinase 2 phosphorylates and promotes Pin1 protein-dependent promyelocytic leukemia protein turnover. J Biol Chem 286(52):44403–44411Google Scholar
  236. 236.
    Amatangelo MD, Goodyear S, Varma D, Stearns ME (2012) c-Myc expression and MEK1-­induced Erk2 nuclear localization are required for TGF-beta induced epithelial-mesenchymal transition and invasion in prostate cancer. Carcinogenesis 33(10):1965–1975Google Scholar
  237. 237.
    Wang H, Song K, Sponseller TL, Danielpour D (2005) Novel function of androgen receptor-­associated protein 55/Hic-5 as a negative regulator of Smad3 signaling. J Biol Chem 280(7):5154–5162Google Scholar
  238. 238.
    Wang H, Song K, Krebs TL, Yang J, Danielpour D (2008) Smad7 is inactivated through a direct physical interaction with the LIM protein Hic-5/ARA55. Oncogene 27(54):6791–6805Google Scholar
  239. 239.
    Shola DT, Wang H, Wahdan-Alaswad R, Danielpour D (2012) Hic-5 controls BMP4 responses in prostate cancer cells through interacting with Smads 1, 5 and 8. Oncogene 31(19):2480–2490Google Scholar
  240. 240.
    Li X, Martinez-Ferrer M, Botta V, Uwamariya C, Banerjee J, Bhowmick NA (2011) Epithelial Hic-5/ARA55 expression contributes to prostate tumorigenesis and castrate responsiveness. Oncogene 30(2):167–177Google Scholar
  241. 241.
    Zhu ML, Kyprianou N (2010) Role of androgens and the androgen receptor in epithelial-­mesenchymal transition and invasion of prostate cancer cells. FASEB J 24(3):769–777Google Scholar
  242. 242.
    Ivanovic V, Melman A, Davis-Joseph B, Valcic M, Geliebter J (1995) Elevated plasma levels of TGF-beta 1 in patients with invasive prostate cancer. Nat Med 1(4):282–284Google Scholar
  243. 243.
    Wolff JM, Fandel T, Borchers H, Brehmer B Jr, Jakse G (1998) Transforming growth factor-­beta1 serum concentration in patients with prostatic cancer and benign prostatic hyperplasia. Br J Urol 81(3):403–405Google Scholar
  244. 244.
    Adler HL, McCurdy MA, Kattan MW, Timme TL, Scardino PT, Thompson TC (1999) Elevated levels of circulating interleukin-6 and transforming growth factor-beta1 in patients with metastatic prostatic carcinoma. J Urol 161(1):182–187Google Scholar
  245. 245.
    Shariat SF, Shalev M, Menesses-Diaz A, Kim IY, Kattan MW, Wheeler TM et al (2001) Preoperative plasma levels of transforming growth factor beta(1) (TGF-beta(1)) strongly predict progression in patients undergoing radical prostatectomy. J Clin Oncol 19(11):2856–2864Google Scholar
  246. 246.
    Sinnreich O, Kratzsch J, Reichenbach A, Glaser C, Huse K, Birkenmeier G (2004) Plasma levels of transforming growth factor-1beta and alpha2-macroglobulin before and after radical prostatectomy: association to clinicopathological parameters. Prostate 61(3):201–208Google Scholar
  247. 247.
    Shariat SF, Kattan MW, Traxel E, Andrews B, Zhu K, Wheeler TM et al (2004) Association of pre- and postoperative plasma levels of transforming growth factor beta(1) and interleukin 6 and its soluble receptor with prostate cancer progression. Clin Cancer Res 10(6):1992–1999Google Scholar
  248. 248.
    Baselga J, Rothenberg ML, Tabernero J, Seoane J, Daly T, Cleverly A et al (2008) TGF-beta signalling-related markers in cancer patients with bone metastasis. Biomarkers 13(2):217–236Google Scholar
  249. 249.
    Svatek RS, Jeldres C, Karakiewicz PI, Suardi N, Walz J, Roehrborn CG et al (2009) Pre-­treatment biomarker levels improve the accuracy of post-prostatectomy nomogram for prediction of biochemical recurrence. Prostate 69(8):886–894Google Scholar
  250. 250.
    Connolly EC, Freimuth J, Akhurst RJ (2012) Complexities of TGF-beta targeted cancer ­therapy. Int J Biol Sci 8(7):964–978Google Scholar
  251. 251.
    Roberts AB, Wakefield LM (2003) The two faces of transforming growth factor beta in carcinogenesis. Proc Natl Acad Sci USA 100(15):8621–8623Google Scholar
  252. 252.
    Yang YA, Dukhanina O, Tang B, Mamura M, Letterio JJ, MacGregor J et al (2002) Lifetime exposure to a soluble TGF-beta antagonist protects mice against metastasis without adverse side effects. J Clin Invest 109(12):1607–1615Google Scholar
  253. 253.
    Bandyopadhyay A, Lopez-Casillas F, Malik SN, Montiel JL, Mendoza V, Yang J et al (2002) Antitumor activity of a recombinant soluble betaglycan in human breast cancer xenograft. Cancer Res 62(16):4690–4695Google Scholar
  254. 254.
    Seth P, Wang ZG, Pister A, Zafar MB, Kim S, Guise T et al (2006) Development of oncolytic adenovirus armed with a fusion of soluble transforming growth factor-beta receptor II and human immunoglobulin Fc for breast cancer therapy. Hum Gene Ther 17(11):1152–1160Google Scholar
  255. 255.
    Hu Z, Zhang Z, Guise T, Seth P (2010) Systemic delivery of an oncolytic adenovirus expressing soluble transforming growth factor-beta receptor II-Fc fusion protein can inhibit breast cancer bone metastasis in a mouse model. Hum Gene Ther 21(11):1623–1629Google Scholar
  256. 256.
    Seth P, Hu Z, Gupta J, Zhang Z, Gerseny H, Berg A et al (2012) systemic delivery of oncolytic adenoviruses targeting transforming growth factor beta inhibits established bone metastasis in a prostate cancer mouse model. Hum Gene Ther 23(8):871–882Google Scholar
  257. 257.
    Nam JS, Terabe M, Kang MJ, Chae H, Voong N, Yang YA et al (2008) Transforming growth factor beta subverts the immune system into directly promoting tumor growth through interleukin-­17. Cancer Res 68(10):3915–3923Google Scholar
  258. 258.
    Mead AL, Wong TT, Cordeiro MF, Anderson IK, Khaw PT (2003) Evaluation of anti-TGF-­beta2 antibody as a new postoperative anti-scarring agent in glaucoma surgery. Invest Ophthalmol Vis Sci 44(8):3394–3401Google Scholar
  259. 259.
    Thompson JE, Vaughan TJ, Williams AJ, Wilton J, Johnson KS, Bacon L et al (1999) A fully human antibody neutralising biologically active human TGFbeta2 for use in therapy. J Immunol Methods 227(1–2):17–29Google Scholar
  260. 260.
    Lonning S, Mannick J, McPherson JM (2011) Antibody targeting of TGF-beta in cancer patients. Curr Pharm Biotechnol 12(12):2176–2189Google Scholar
  261. 261.
    Hau P, Jachimczak P, Schlingensiepen R, Schulmeyer F, Jauch T, Steinbrecher A et al (2007) Inhibition of TGF-beta2 with AP 12009 in recurrent malignant gliomas: from preclinical to phase I/II studies. Oligonucleotides 17(2):201–212Google Scholar
  262. 262.
    Laping NJ, Grygielko E, Mathur A, Butter S, Bomberger J, Tweed C et al (2002) Inhibition of transforming growth factor (TGF)-beta1-induced extracellular matrix with a novel inhibitor of the TGF-beta type I receptor kinase activity: SB-431542. Mol Pharmacol 62(1):58–64Google Scholar
  263. 263.
    Ehata S, Hanyu A, Fujime M, Katsuno Y, Fukunaga E, Goto K et al (2007) Ki26894, a novel transforming growth factor-beta type I receptor kinase inhibitor, inhibits in vitro invasion and in vivo bone metastasis of a human breast cancer cell line. Cancer Sci 98(1):127–133Google Scholar
  264. 264.
    Bandyopadhyay A, Agyin JK, Wang L, Tang Y, Lei X, Story BM et al (2006) Inhibition of pulmonary and skeletal metastasis by a transforming growth factor-beta type I receptor kinase inhibitor. Cancer Res 66(13):6714–6721Google Scholar
  265. 265.
    Mohammad KS, Javelaud D, Fournier PG, Niewolna M, McKenna CR, Peng XH et al (2011) TGF-beta-RI kinase inhibitor SD-208 reduces the development and progression of melanoma bone metastases. Cancer Res 71(1):175–184Google Scholar
  266. 266.
    Zhang B, Halder SK, Zhang S, Datta PK (2009) Targeting transforming growth factor-beta signaling in liver metastasis of colon cancer. Cancer Lett 277(1):114–120Google Scholar
  267. 267.
    Melisi D, Ishiyama S, Sclabas GM, Fleming JB, Xia Q, Tortora G et al (2008) LY2109761, a novel transforming growth factor beta receptor type I and type II dual inhibitor, as a therapeutic approach to suppressing pancreatic cancer metastasis. Mol Cancer Ther 7(4):829–840Google Scholar
  268. 268.
    Korpal M, Yan J, Lu X, Xu S, Lerit DA, Kang Y (2009) Imaging transforming growth factor-­beta signaling dynamics and therapeutic response in breast cancer bone metastasis. Nat Med 15(8):960–966Google Scholar
  269. 269.
    Wan X, Li ZG, Yingling JM, Yang J, Starbuck MW, Ravoori MK et al (2012) Effect of ­transforming growth factor beta (TGF-beta) receptor I kinase inhibitor on prostate cancer bone growth. Bone 50(3):695–703Google Scholar
  270. 270.
    Vogt J, Traynor R, Sapkota GP (2011) The specificities of small molecule inhibitors of the TGFss and BMP pathways. Cell Signal 23(11):1831–1842Google Scholar
  271. 271.
    Zhao BM, Hoffmann FM (2006) Inhibition of transforming growth factor-beta1-induced signaling and epithelial-to-mesenchymal transition by the Smad-binding peptide aptamer Trx-­SARA. Mol Biol Cell 17(9):3819–3831Google Scholar

Copyright information

© Mayo Clinic 2013

Authors and Affiliations

  1. 1.Division of General Medical Sciences, Department of Pharmacology, Case Comprehensive Cancer CenterCase Western University School of MedicineClevelandUSA
  2. 2.Department of UrologyUniversity Hospitals of ClevelandClevelandUSA

Personalised recommendations