Skip to main content
SpringerLink
Log in

Interplay Among PI3K/AKT, PTEN/FOXO and AR Signaling in Prostate Cancer

  • Chapter
  • First Online:
Prostate Cancer

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1210))

Abstract

The PI3K signaling pathway is activated in a majority of cancer types. It promotes tumorigenesis by regulating nutrient metabolism, cell proliferation, survival, migration, and angiogenesis. The underlying mechanisms of PI3K/AKT activation are mainly due to deletions or mutations in its key negative regulator gene—PTEN. However, mutations in other pathway genes, such as the tumor suppressor gene SPOP, may contribute indirectly to the activation of this pathway. Interestingly, a mutually exclusive relationship exists between genomic alterations in PTEN and mutations in SPOP in prostate cancer patients, suggesting that altered functions of these two tumor suppressors might share similar or at least partially overlapping mechanisms in tumorigenesis. Activated AKT can phosphorylate directly a number of downstream effectors and thereby inhibit or activate their functions. An important target of PI3K/AKT signaling is FOXO1 protein that can be phosphorylated directly by AKT leading to translocation of FOXO1 from the cytoplasm to the nucleus. This not only impairs FOXO1 activities on transactivation of downstream target genes, but also abolishes its transcriptional activity-independent inhibitory effect on other targets such as AR, ERG and RUNX2. Interestingly, heterozygous deletion of Pten, or mutation of Spop alone has minimal effects on tumorigenesis in the mouse prostate, suggesting that PI3K/AKT pathway interacts with other pathways to drive prostate cancer progression. Indeed, the cross talk between PI3K/AKT and other pathways, such as AR, WNT, and ERK signaling pathways is known to play essential roles in disease progression and drug resistance in prostate cancer. Therefore, co-targeting the PI3K/AKT signaling pathway and its cooperating pathways may be critical for improving the anti-cancer efficacy of PI3K/AKT inhibitors in the clinic.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 189.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 249.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 249.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. P. Liu, H. Cheng, T.M. Roberts, J.J. Zhao, Targeting the phosphoinositide 3-kinase pathway in cancer. Nat. Rev. Drug Discov. 8, 627–644 (2009)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. E. Gonzalez, T.E. McGraw, The Akt kinases: isoform specificity in metabolism and cancer. Cell Cycle 8, 2502–2508 (2009)

    Article  CAS  PubMed  Google Scholar 

  3. D.R. Alessi, S.R. James, C.P. Downes, A.B. Holmes, P.R. Gaffney, C.B. Reese, P. Cohen, Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Balpha. Curr. Biol. 7, 261–269 (1997)

    Article  CAS  PubMed  Google Scholar 

  4. D.D. Sarbassov, D.A. Guertin, S.M. Ali, D.M. Sabatini, Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307, 1098–1101 (2005)

    Article  CAS  PubMed  Google Scholar 

  5. B.S. Carver, C. Chapinski, J. Wongvipat, H. Hieronymus, Y. Chen, S. Chandarlapaty, V.K. Arora, C. Le, J. Koutcher, H. Scher, et al., Reciprocal feedback regulation of PI3K and androgen receptor signaling in PTEN-deficient prostate cancer. Cancer Cell 19, 575–586 (2011)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. B.S. Taylor, N. Schultz, H. Hieronymus, A. Gopalan, Y. Xiao, B.S. Carver, V.K. Arora, P. Kaushik, E. Cerami, B. Reva, et al., Integrative genomic profiling of human prostate cancer. Cancer Cell 18, 11–22 (2010)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. V.A. Rafalski, A. Brunet, Energy metabolism in adult neural stem cell fate. Prog. Neurobiol. 93, 182–203 (2011)

    Article  CAS  PubMed  Google Scholar 

  8. L. Ojeda, J. Gao, K.G. Hooten, E. Wang, J.R. Thonhoff, T.J. Dunn, T. Gao, P. Wu, Critical role of PI3K/Akt/GSK3beta in motoneuron specification from human neural stem cells in response to FGF2 and EGF. PLoS One 6, e23414 (2011)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. J. Peltier, A. O’Neill, D.V. Schaffer, PI3K/Akt and CREB regulate adult neural hippocampal progenitor proliferation and differentiation. Dev. Neurobiol. 67, 1348–1361 (2007)

    Article  CAS  PubMed  Google Scholar 

  10. B.D. Manning, A. Toker, AKT/PKB signaling: navigating the network. Cell 169, 381–405 (2017)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. K. Du, M. Montminy, CREB is a regulatory target for the protein kinase Akt/PKB. J. Biol. Chem. 273, 32377–32379 (1998)

    Article  CAS  PubMed  Google Scholar 

  12. J.R. Graff, B.W. Konicek, A.M. McNulty, Z. Wang, K. Houck, S. Allen, J.D. Paul, A. Hbaiu, R.G. Goode, G.E. Sandusky, et al., Increased AKT activity contributes to prostate cancer progression by dramatically accelerating prostate tumor growth and diminishing p27Kip1 expression. J. Biol. Chem. 275, 24500–24505 (2000)

    Article  CAS  PubMed  Google Scholar 

  13. I. Shin, F.M. Yakes, F. Rojo, N.Y. Shin, A.V. Bakin, J. Baselga, C.L. Arteaga, PKB/Akt mediates cell-cycle progression by phosphorylation of p27(Kip1) at threonine 157 and modulation of its cellular localization. Nat. Med. 8, 1145–1152 (2002)

    Article  CAS  PubMed  Google Scholar 

  14. A. Brunet, A. Bonni, M.J. Zigmond, M.Z. Lin, P. Juo, L.S. Hu, M.J. Anderson, K.C. Arden, J. Blenis, M.E. Greenberg, Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 96, 857–868 (1999)

    Article  CAS  PubMed  Google Scholar 

  15. X. Zhang, N. Tang, T.J. Hadden, A.K. Rishi, Akt, FoxO and regulation of apoptosis. Biochim. Biophys. Acta 1813, 1978–1986 (2011b)

    Article  CAS  PubMed  Google Scholar 

  16. K. Hara, K. Yonezawa, M.T. Kozlowski, T. Sugimoto, K. Andrabi, Q.P. Weng, M. Kasuga, I. Nishimoto, J. Avruch, Regulation of eIF-4E BP1 phosphorylation by mTOR. J. Biol. Chem. 272, 26457–26463 (1997)

    Article  CAS  PubMed  Google Scholar 

  17. B.D. Manning, L.C. Cantley, AKT/PKB signaling: navigating downstream. Cell 129, 1261–1274 (2007)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. N. Chalhoub, S.J. Baker, PTEN and the PI3-kinase pathway in cancer. Annu. Rev. Pathol. 4, 127–150 (2009)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Cancer Genome Atlas Research Network Network, The molecular taxonomy of primary prostate cancer. Cell 163, 1011–1025 (2015)

    Article  CAS  Google Scholar 

  20. D. Robinson, E.M. Van Allen, Y.M. Wu, N. Schultz, R.J. Lonigro, J.M. Mosquera, B. Montgomery, M.E. Taplin, C.C. Pritchard, G. Attard, et al., Integrative clinical genomics of advanced prostate cancer. Cell 162, 454 (2015)

    Article  CAS  PubMed  Google Scholar 

  21. S. Wee, D. Wiederschain, S.M. Maira, A. Loo, C. Miller, R. deBeaumont, F. Stegmeier, Y.M. Yao, C. Lengauer, PTEN-deficient cancers depend on PIK3CB. Proc. Natl. Acad. Sci. U. S. A. 105, 13057–13062 (2008)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. J. Armenia, S.A.M. Wankowicz, D. Liu, J. Gao, R. Kundra, E. Reznik, W.K. Chatila, D. Chakravarty, G.C. Han, I. Coleman, et al., The long tail of oncogenic drivers in prostate cancer. Nat. Genet. 50, 645–651 (2018)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. A. Suzuki, J.L. de la Pompa, V. Stambolic, A.J. Elia, T. Sasaki, I. del Barco Barrantes, A. Ho, A. Wakeham, A. Itie, W. Khoo, et al., High cancer susceptibility and embryonic lethality associated with mutation of the PTEN tumor suppressor gene in mice. Curr. Biol. 8, 1169–1178 (1998)

    Article  CAS  PubMed  Google Scholar 

  24. L.C. Trotman, M. Niki, Z.A. Dotan, J.A. Koutcher, A. Di Cristofano, A. Xiao, A.S. Khoo, P. Roy-Burman, N.M. Greenberg, T. Van Dyke, et al., Pten dose dictates cancer progression in the prostate. PLoS Biol. 1, E59 (2003)

    Article  PubMed  PubMed Central  Google Scholar 

  25. S. Wang, J. Gao, Q. Lei, N. Rozengurt, C. Pritchard, J. Jiao, G.V. Thomas, G. Li, P. Roy-Burman, P.S. Nelson, et al., Prostate-specific deletion of the murine Pten tumor suppressor gene leads to metastatic prostate cancer. Cancer Cell 4, 209–221 (2003)

    Article  CAS  PubMed  Google Scholar 

  26. A. Di Cristofano, M. De Acetis, A. Koff, C. Cordon-Cardo, P.P. Pandolfi, Pten and p27KIP1 cooperate in prostate cancer tumor suppression in the mouse. Nat. Genet. 27, 222–224 (2001)

    Article  PubMed  CAS  Google Scholar 

  27. M.J. Kim, R.D. Cardiff, N. Desai, W.A. Banach-Petrosky, R. Parsons, M.M. Shen, C. Abate-Shen, Cooperativity of Nkx3.1 and Pten loss of function in a mouse model of prostate carcinogenesis. Proc. Natl. Acad. Sci. U. S. A. 99, 2884–2889 (2002)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. B.S. Carver, J. Tran, A. Gopalan, Z. Chen, S. Shaikh, A. Carracedo, A. Alimonti, C. Nardella, S. Varmeh, P.T. Scardino, et al., Aberrant ERG expression cooperates with loss of PTEN to promote cancer progression in the prostate. Nat. Genet. 41, 619–624 (2009)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. J.C. King, J. Xu, J. Wongvipat, H. Hieronymus, B.S. Carver, D.H. Leung, B.S. Taylor, C. Sander, R.D. Cardiff, S.S. Couto, et al., Cooperativity of TMPRSS2-ERG with PI3-kinase pathway activation in prostate oncogenesis. Nat. Genet. 41, 524–526 (2009)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. L. Ding, S. Chen, P. Liu, Y. Pan, J. Zhong, K.M. Regan, L. Wang, C. Yu, A. Rizzardi, L. Cheng, et al., CBP loss cooperates with PTEN haploinsufficiency to drive prostate cancer: implications for epigenetic therapy. Cancer Res. 74, 2050–2061 (2014)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. C.E. Barbieri, S.C. Baca, M.S. Lawrence, F. Demichelis, M. Blattner, J.P. Theurillat, T.A. White, P. Stojanov, E. Van Allen, N. Stransky, et al., Exome sequencing identifies recurrent SPOP, FOXA1 and MED12 mutations in prostate cancer. Nat. Genet. 44, 685–689 (2012)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. J. An, S. Ren, S.J. Murphy, S. Dalangood, C. Chang, X. Pang, Y. Cui, L. Wang, Y. Pan, X. Zhang, et al., Truncated ERG oncoproteins from TMPRSS2-ERG fusions are resistant to SPOP-mediated proteasome degradation. Mol. Cell 59, 904–916 (2015)

    Article  CAS  PubMed  Google Scholar 

  33. J. An, C. Wang, Y. Deng, L. Yu, H. Huang, Destruction of full-length androgen receptor by wild-type SPOP, but not prostate-cancer-associated mutants. Cell Rep. 6, 657–669 (2014)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. M. Blattner, D.J. Lee, C. O’Reilly, K. Park, T.Y. MacDonald, F. Khani, K.R. Turner, Y.L. Chiu, P.J. Wild, I. Dolgalev, et al., SPOP mutations in prostate cancer across demographically diverse patient cohorts. Neoplasia 16, 14–20 (2014)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. C. Geng, B. He, L. Xu, C.E. Barbieri, V.K. Eedunuri, S.A. Chew, M. Zimmermann, R. Bond, J. Shou, C. Li, et al., Prostate cancer-associated mutations in speckle-type POZ protein (SPOP) regulate steroid receptor coactivator 3 protein turnover. Proc. Natl. Acad. Sci. U. S. A. 110, 6997–7002 (2013)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. C. Geng, K. Rajapakshe, S.S. Shah, J. Shou, V.K. Eedunuri, C. Foley, W. Fiskus, M. Rajendran, S.A. Chew, M. Zimmermann, et al., Androgen receptor is the key transcriptional mediator of the tumor suppressor SPOP in prostate cancer. Cancer Res. 74, 5631–5643 (2014)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. A.C. Groner, L. Cato, J. de Tribolet-Hardy, T. Bernasocchi, H. Janouskova, D. Melchers, R. Houtman, A.C.B. Cato, P. Tschopp, L. Gu, et al., TRIM24 is an oncogenic transcriptional activator in prostate cancer. Cancer Cell 29, 846–858 (2016)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. C. Li, J. Ao, J. Fu, D.F. Lee, J. Xu, D. Lonard, B.W. O’Malley, Tumor-suppressor role for the SPOP ubiquitin ligase in signal-dependent proteolysis of the oncogenic co-activator SRC-3/AIB1. Oncogene 30, 4350–4364 (2011)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Y. Yan, J. An, Y. Yang, D. Wu, Y. Bai, W. Cao, L. Ma, J. Chen, Z. Yu, Y. He, et al., Dual inhibition of AKT-mTOR and AR signaling by targeting HDAC3 in PTEN- or SPOP-mutated prostate cancer. EMBO Mol. Med. 10, e8478 (2018)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. P. Zhang, D. Wang, Y. Zhao, S. Ren, K. Gao, Z. Ye, S. Wang, C.W. Pan, Y. Zhu, Y. Yan, et al., Intrinsic BET inhibitor resistance in SPOP-mutated prostate cancer is mediated by BET protein stabilization and AKT-mTORC1 activation. Nat. Med. 23, 1055–1062 (2017)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. A. Saci, L.C. Cantley, C.L. Carpenter, Rac1 regulates the activity of mTORC1 and mTORC2 and controls cellular size. Mol. Cell 42, 50–61 (2011)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. R. Lasserre, X.J. Guo, F. Conchonaud, Y. Hamon, O. Hawchar, A.M. Bernard, S.M. Soudja, P.F. Lenne, H. Rigneault, D. Olive, et al., Raft nanodomains contribute to Akt/PKB plasma membrane recruitment and activation. Nat. Chem. Biol. 4, 538–547 (2008)

    Article  CAS  PubMed  Google Scholar 

  43. L. Zhuang, J. Lin, M.L. Lu, K.R. Solomon, M.R. Freeman, Cholesterol-rich lipid rafts mediate akt-regulated survival in prostate cancer cells. Cancer Res. 62, 2227–2231 (2002)

    CAS  PubMed  Google Scholar 

  44. J. Xu, L. Liao, G. Ning, H. Yoshida-Komiya, C. Deng, B.W. O’Malley, The steroid receptor coactivator SRC-3 (p/CIP/RAC3/AIB1/ACTR/TRAM-1) is required for normal growth, puberty, female reproductive function, and mammary gland development. Proc. Natl. Acad. Sci. U. S. A. 97, 6379–6384 (2000)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. L.H. Zhang, A.A. Yin, J.X. Cheng, H.Y. Huang, X.M. Li, Y.Q. Zhang, N. Han, X. Zhang, TRIM24 promotes glioma progression and enhances chemoresistance through activation of the PI3K/Akt signaling pathway. Oncogene 34, 600–610 (2015)

    Article  CAS  PubMed  Google Scholar 

  46. M. Blattner, D. Liu, B.D. Robinson, D. Huang, A. Poliakov, D. Gao, S. Nataraj, L.D. Deonarine, M.A. Augello, V. Sailer, et al., SPOP mutation drives prostate tumorigenesis in vivo through coordinate regulation of PI3K/mTOR and AR signaling. Cancer Cell 31, 436–451 (2017)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. H. Huang, D.J. Tindall, Dynamic FoxO transcription factors. J. Cell Sci. 120, 2479–2487 (2007)

    Article  CAS  PubMed  Google Scholar 

  48. Y. Zhao, D.J. Tindall, H. Huang, Modulation of androgen receptor by FOXA1 and FOXO1 factors in prostate cancer. Int. J. Biol. Sci. 10, 614–619 (2014)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. X.Y. Dong, C. Chen, X. Sun, P. Guo, R.L. Vessella, R.X. Wang, L.W. Chung, W. Zhou, J.T. Dong, FOXO1A is a candidate for the 13q14 tumor suppressor gene inhibiting androgen receptor signaling in prostate cancer. Cancer Res. 66, 6998–7006 (2006)

    Article  CAS  PubMed  Google Scholar 

  50. B.S. Haflidadottir, O. Larne, M. Martin, M. Persson, A. Edsjo, A. Bjartell, Y. Ceder, Upregulation of miR-96 enhances cellular proliferation of prostate cancer cells through FOXO1. PLoS One 8, e72400 (2013)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. V. Modur, R. Nagarajan, B.M. Evers, J. Milbrandt, FOXO proteins regulate tumor necrosis factor-related apoptosis inducing ligand expression. Implications for PTEN mutation in prostate cancer. J. Biol. Chem. 277, 47928–47937 (2002)

    Article  CAS  PubMed  Google Scholar 

  52. Y. Yang, H. Hou, E.M. Haller, S.V. Nicosia, W. Bai, Suppression of FOXO1 activity by FHL2 through SIRT1-mediated deacetylation. EMBO J. 24, 1021–1032 (2005)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. L.R. Bohrer, P. Liu, J. Zhong, Y. Pan, J. Angstman, L.J. Brand, S.M. Dehm, H. Huang, FOXO1 binds to the TAU5 motif and inhibits constitutively active androgen receptor splice variants. Prostate 73, 1017–1027 (2013)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. W. Fan, T. Yanase, H. Morinaga, T. Okabe, M. Nomura, H. Daitoku, A. Fukamizu, S. Kato, R. Takayanagi, H. Nawata, Insulin-like growth factor 1/insulin signaling activates androgen signaling through direct interactions of Foxo1 with androgen receptor. J. Biol. Chem. 282, 7329–7338 (2007)

    Article  CAS  PubMed  Google Scholar 

  55. P. Liu, S. Li, L. Gan, T.P. Kao, H. Huang, A transcription-independent function of FOXO1 in inhibition of androgen-independent activation of the androgen receptor in prostate cancer cells. Cancer Res. 68, 10290–10299 (2008)

    Article  CAS  PubMed  Google Scholar 

  56. S.N. Mediwala, H. Sun, A.T. Szafran, S.M. Hartig, G. Sonpavde, T.G. Hayes, P. Thiagarajan, M.A. Mancini, M. Marcelli, The activity of the androgen receptor variant AR-V7 is regulated by FOXO1 in a PTEN-PI3K-AKT-dependent way. Prostate 73, 267–277 (2013)

    Article  CAS  PubMed  Google Scholar 

  57. H.K. Lin, S. Yeh, H.Y. Kang, C. Chang, Akt suppresses androgen-induced apoptosis by phosphorylating and inhibiting androgen receptor. Proc. Natl. Acad. Sci. U. S. A. 98, 7200–7205 (2001)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. P. Adamo, M.R. Ladomery, The oncogene ERG: a key factor in prostate cancer. Oncogene 35, 403–414 (2016)

    Article  CAS  PubMed  Google Scholar 

  59. S.A. Tomlins, D.R. Rhodes, S. Perner, S.M. Dhanasekaran, R. Mehra, X.W. Sun, S. Varambally, X. Cao, J. Tchinda, R. Kuefer, et al., Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science 310, 644–648 (2005)

    Article  CAS  PubMed  Google Scholar 

  60. Y. Yang, A.M. Blee, D. Wang, J. An, Y. Pan, Y. Yan, T. Ma, Y. He, J. Dugdale, X. Hou, et al., Loss of FOXO1 cooperates with TMPRSS2-ERG overexpression to promote prostate tumorigenesis and cell invasion. Cancer Res. 77, 6524–6537 (2017)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. I.A. San Martin, N. Varela, M. Gaete, K. Villegas, M. Osorio, J.C. Tapia, M. Antonelli, E.E. Mancilla, B.P. Pereira, S.S. Nathan, et al., Impaired cell cycle regulation of the osteoblast-related heterodimeric transcription factor Runx2-Cbfbeta in osteosarcoma cells. J. Cell. Physiol. 221, 560–571 (2009)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. D. Wysokinski, E. Pawlowska, J. Blasiak, RUNX2: a master bone growth regulator that may be involved in the DNA damage response. DNA Cell Biol. 34, 305–315 (2015)

    Article  CAS  PubMed  Google Scholar 

  63. J.J. Westendorf, S.K. Zaidi, J.E. Cascino, R. Kahler, A.J. van Wijnen, J.B. Lian, M. Yoshida, G.S. Stein, X. Li, Runx2 (Cbfa1, AML-3) interacts with histone deacetylase 6 and represses the p21(CIP1/WAF1) promoter. Mol. Cell. Biol. 22, 7982–7992 (2002)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. C. Ge, G. Xiao, D. Jiang, Q. Yang, N.E. Hatch, H. Roca, R.T. Franceschi, Identification and functional characterization of ERK/MAPK phosphorylation sites in the Runx2 transcription factor. J. Biol. Chem. 284, 32533–32543 (2009)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. M. Qiao, P. Shapiro, M. Fosbrink, H. Rus, R. Kumar, A. Passaniti, Cell cycle-dependent phosphorylation of the RUNX2 transcription factor by cdc2 regulates endothelial cell proliferation. J. Biol. Chem. 281, 7118–7128 (2006)

    Article  CAS  PubMed  Google Scholar 

  66. C. Ge, G. Zhao, Y. Li, H. Li, X. Zhao, G. Pannone, P. Bufo, A. Santoro, F. Sanguedolce, S. Tortorella, et al., Role of Runx2 phosphorylation in prostate cancer and association with metastatic disease. Oncogene 35, 366–376 (2016)

    Article  CAS  PubMed  Google Scholar 

  67. S.K. Baniwal, O. Khalid, D. Sir, G. Buchanan, G.A. Coetzee, B. Frenkel, Repression of Runx2 by androgen receptor (AR) in osteoblasts and prostate cancer cells: AR binds Runx2 and abrogates its recruitment to DNA. Mol. Endocrinol. 23, 1203–1214 (2009)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. H. Kawate, Y. Wu, K. Ohnaka, R. Takayanagi, Mutual transactivational repression of Runx2 and the androgen receptor by an impairment of their normal compartmentalization. J. Steroid Biochem. Mol. Biol. 105, 46–56 (2007)

    Article  CAS  PubMed  Google Scholar 

  69. H. Zhang, Y. Pan, L. Zheng, C. Choe, B. Lindgren, E.D. Jensen, J.J. Westendorf, L. Cheng, H. Huang, FOXO1 inhibits Runx2 transcriptional activity and prostate cancer cell migration and invasion. Cancer Res. 71, 3257–3267 (2011a)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. S. Yang, H. Xu, S. Yu, H. Cao, J. Fan, C. Ge, R.T. Fransceschi, H.H. Dong, G. Xiao, Foxo1 mediates insulin-like growth factor 1 (IGF1)/insulin regulation of osteocalcin expression by antagonizing Runx2 in osteoblasts. J. Biol. Chem. 286, 19149–19158 (2011)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Y. Yang, Y. Bai, Y. He, Y. Zhao, J. Chen, L. Ma, Y. Pan, M. Hinten, J. Zhang, R.J. Karnes, et al., PTEN loss promotes intratumoral androgen synthesis and tumor microenvironment remodeling via aberrant activation of RUNX2 in castration-resistant prostate cancer. Clin. Cancer Res. 24, 834–846 (2018)

    Article  CAS  PubMed  Google Scholar 

  72. D.J. Mulholland, L.M. Tran, Y. Li, H. Cai, A. Morim, S. Wang, S. Plaisier, I.P. Garraway, J. Huang, T.G. Graeber, H. Wu, Cell autonomous role of PTEN in regulating castration-resistant prostate cancer growth. Cancer Cell 19, 792–804 (2011)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. J. Long, W.Y. Fang, L. Chang, W.H. Gao, Y. Shen, M.Y. Jia, Y.X. Zhang, Y. Wang, H.B. Dou, W.J. Zhang, et al., Targeting HDAC3, a new partner protein of AKT in the reversal of chemoresistance in acute myeloid leukemia via DNA damage response. Leukemia 31, 2761–2770 (2017)

    Article  CAS  PubMed  Google Scholar 

  74. D.S. Welsbie, J. Xu, Y. Chen, L. Borsu, H.I. Scher, N. Rosen, C.L. Sawyers, Histone deacetylases are required for androgen receptor function in hormone-sensitive and castrate-resistant prostate cancer. Cancer Res. 69, 958–966 (2009)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. V. Murillo-Garzon, R. Kypta, WNT signalling in prostate cancer. Nat. Rev. Urol. 14, 683–696 (2017)

    Article  CAS  PubMed  Google Scholar 

  76. D. Fang, D. Hawke, Y. Zheng, Y. Xia, J. Meisenhelder, H. Nika, G.B. Mills, R. Kobayashi, T. Hunter, Z. Lu, Phosphorylation of beta-catenin by AKT promotes beta-catenin transcriptional activity. J. Biol. Chem. 282, 11221–11229 (2007)

    Article  CAS  PubMed  Google Scholar 

  77. S.A. Tahir, G. Yang, A. Goltsov, K.D. Song, C. Ren, J. Wang, W. Chang, T.C. Thompson, Caveolin-1-LRP6 signaling module stimulates aerobic glycolysis in prostate cancer. Cancer Res. 73, 1900–1911 (2013)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. G. Thyssen, T.H. Li, L. Lehmann, M. Zhuo, M. Sharma, Z. Sun, LZTS2 is a novel beta-catenin-interacting protein and regulates the nuclear export of beta-catenin. Mol. Cell. Biol. 26, 8857–8867 (2006)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. E.J. Yu, E. Hooker, D.T. Johnson, M.K. Kwak, K. Zou, R. Luong, Y. He, Z. Sun, LZTS2 and PTEN collaboratively regulate ss-catenin in prostatic tumorigenesis. PLoS One 12, e0174357 (2017)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  80. H. Gao, X. Ouyang, W.A. Banach-Petrosky, W.L. Gerald, M.M. Shen, C. Abate-Shen, Combinatorial activities of Akt and B-Raf/Erk signaling in a mouse model of androgen-independent prostate cancer. Proc. Natl. Acad. Sci. U. S. A. 103, 14477–14482 (2006)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. S. Chandarlapaty, A. Sawai, M. Scaltriti, V. Rodrik-Outmezguine, O. Grbovic-Huezo, V. Serra, P.K. Majumder, J. Baselga, N. Rosen, AKT inhibition relieves feedback suppression of receptor tyrosine kinase expression and activity. Cancer Cell 19, 58–71 (2011)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. V. Serra, M. Scaltriti, L. Prudkin, P.J. Eichhorn, Y.H. Ibrahim, S. Chandarlapaty, B. Markman, O. Rodriguez, M. Guzman, S. Rodriguez, et al., PI3K inhibition results in enhanced HER signaling and acquired ERK dependency in HER2-overexpressing breast cancer. Oncogene 30, 2547–2557 (2011)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. C.W. Pan, X. Jin, Y. Zhao, Y. Pan, J. Yang, R.J. Karnes, J. Zhang, L. Wang, H. Huang, AKT-phosphorylated FOXO1 suppresses ERK activation and chemoresistance by disrupting IQGAP1-MAPK interaction. EMBO J. 36, 995–1010 (2017)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. M. Crumbaker, L. Khoja, A.M. Joshua, AR signaling and the PI3K pathway in prostate cancer. Cancers (Basel) 9, E34 (2017)

    Article  CAS  Google Scholar 

  85. T. McHardy, J.J. Caldwell, K.M. Cheung, L.J. Hunter, K. Taylor, M. Rowlands, R. Ruddle, A. Henley, A. de Haven Brandon, M. Valenti, et al., Discovery of 4-amino-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamides as selective, orally active inhibitors of protein kinase B (Akt). J. Med. Chem. 53, 2239–2249 (2010)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. J.C. Bendell, A.M. Varghese, D.M. Hyman, T.M. Bauer, S. Pant, S. Callies, J. Lin, R. Martinez, E. Wickremsinhe, A. Fink, et al., A first-in-human phase 1 study of LY3023414, an oral PI3K/mTOR dual inhibitor, in patients with advanced cancer. Clin. Cancer Res. 24, 3253–3262 (2018)

    Article  CAS  PubMed  Google Scholar 

  87. P. Toren, S. Kim, T. Cordonnier, C. Crafter, B.R. Davies, L. Fazli, M.E. Gleave, A. Zoubeidi, Combination AZD5363 with enzalutamide significantly delays enzalutamide-resistant prostate cancer in preclinical models. Eur. Urol. 67, 986–990 (2015)

    Article  CAS  PubMed  Google Scholar 

  88. A. Zoubeidi, M.E. Gleave, Co-targeting driver pathways in prostate cancer: two birds with one stone. EMBO Mol. Med. 10, e8928 (2018)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine and Science, Rochester, MN, USA

    Yuqian Yan & Haojie Huang

  2. Department of Urology, Mayo Clinic College of Medicine and Science, Rochester, MN, USA

    Haojie Huang

  3. Mayo Clinic Cancer Center, Mayo Clinic College of Medicine and Science, Rochester, MN, USA

    Haojie Huang

Authors
  1. Yuqian Yan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Haojie Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Haojie Huang .

Editor information

Editors and Affiliations

  1. Department of Laboratory Medicine and Pathology, Department of Urology, Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA

    Scott M. Dehm

  2. Departments of Urology, and Biochemistry & Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN, USA

    Donald J. Tindall

Rights and permissions

Reprints and permissions

Copyright information

© 2019 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Yan, Y., Huang, H. (2019). Interplay Among PI3K/AKT, PTEN/FOXO and AR Signaling in Prostate Cancer. In: Dehm, S., Tindall, D. (eds) Prostate Cancer. Advances in Experimental Medicine and Biology, vol 1210. Springer, Cham. https://doi.org/10.1007/978-3-030-32656-2_14

Download citation

Publish with us

Policies and ethics

Search

Navigation