Plant-Derived Isoprenoids Mediate Regulation of mTOR Signaling in Tumor Cells

  • Dennis M. Peffley
  • Patricia Hentosh


It is widely recognized that metabolites derived from plants behave as preemptive nutrients that provide cytoprotection or modify disease risk through processes regulating gene expression at the levels of transcription, DNA methylation as well as formation or bioactivation of proteins. In contrast, lipid-related terpenes, commonly referred to as isoprenoids, are bioactive secondary products of plant mevalonate metabolism that modulate mammalian cell growth, survival, differentiation and autophagic cell death through their effects on gene expression at the level of mRNA translation via the mammalian target of rapamycin (mTOR) pathway. Early findings from our laboratory established that isoprenoids such as perillyl alcohol suppressed 3-hydroxy-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme of mevalonate/cholesterol biosynthesis, through a mechanism regulating mRNA translational efficiency. Additionally, our studies found that perillyl alcohol suppressed 4E-BP1 phosphorylation in tumor cells via the mTOR pathway, and disrupted the m7GpppX mRNA cap binding complex, eIF4F, by suppressing interaction of eukaryotic initiation factor 4E (eIF4E) with eIF4G. Furthermore, isoprenoids exhibit certain rapamycin-like inhibitory effects on the rapamycin-sensitive mTORC1 complex, but also have distinct effects on the rapamycin-insensitive TSC1/2-mediated regulation of mTOR signaling. Overall, these effects on mTOR signaling suppress cap-dependent protein translation and set-up conditions for cap-independent translation that in part mediate isoprenoid-induced tumor cell death through a caspase-independent mechanism similar to autophagy. Additionally, other studies have reported that polyphenols, flavonoids and triterpenes induced cell death through a similar mechanism.


Autophagic Cell Death Sterol Regulatory Element Binding Protein Prostate Tumor Cell Perillyl Alcohol Reductase mRNA 
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.


  1. Abid MR, Li Y et al (1999) Translational regulation of ribonucleotide reductase by eukaryotic initiation factor 4E links protein synthesis to the control of DNA replication. J Biol Chem 274(50):35991–35998PubMedGoogle Scholar
  2. Abraham RT, Gibbons JJ (2007) The mammalian target of rapamycin signaling pathway: twists and turns in the road to cancer therapy. Clin Cancer Res 13(11):3109–3114PubMedGoogle Scholar
  3. Adlercreutz H (1990) Western diet and Western diseases: some hormonal and biochemical mechanisms and associations. Scand J Clin Lab Invest Suppl 201:3–23PubMedGoogle Scholar
  4. Aggarwal BB, Sundaram C et al (2010) Tocotrienols, the vitamin E of the 21st century: its potential against cancer and other chronic diseases. Biochem Pharmacol 80(11):1613–1631PubMedGoogle Scholar
  5. Alhasan SA, Aranha O et al (2001) Genistein elicits pleiotropic molecular effects on head and neck cancer cells. Clin Cancer Res 7(12):4174–4181PubMedGoogle Scholar
  6. Aoki H, Takada Y et al (2007) Evidence that curcumin suppresses the growth of malignant gliomas in vitro and in vivo through induction of autophagy: role of Akt and extracellular signal-regulated kinase signaling pathways. Mol Pharmacol 72(1):29–39PubMedGoogle Scholar
  7. Ariazi EA, Gould MN (1996) Identifying differential gene expression in monoterpene-treated mammary carcinomas using subtractive display. J Biol Chem 271(46):29286–29294PubMedGoogle Scholar
  8. Ariazi EA, Satomi Y et al (1999) Activation of the transforming growth factor beta signaling pathway and induction of cytostasis and apoptosis in mammary carcinomas treated with the anticancer agent perillyl alcohol. Cancer Res 59(8):1917–1928PubMedGoogle Scholar
  9. Averous J, Proud CG (2006) When translation meets transformation: the mTOR story. Oncogene 25(48):6423–6435PubMedGoogle Scholar
  10. Azrolan NI, Coleman PS (1989) A discoordinate increase in the cellular amount of 3-hydroxy-3-methylglutaryl-CoA reductase results in the loss of rate-limiting control over cholesterogenesis in a tumour cell-free system. Biochem J 258(2):421–425PubMedGoogle Scholar
  11. Babendure JR, Babendure JL et al (2006) Control of mammalian translation by mRNA structure near caps. RNA 12(5):851–861PubMedGoogle Scholar
  12. Barthelman M, Chen W et al (1998) Inhibitory effects of perillyl alcohol on UVB-induced murine skin cancer and AP-1 transactivation. Cancer Res 58(4):711–716PubMedGoogle Scholar
  13. Beevers CS, Li F et al (2006) Curcumin inhibits the mammalian target of rapamycin-mediated signaling pathways in cancer cells. Int J Cancer 119(4):757–764PubMedGoogle Scholar
  14. Beevers CS, Chen L et al (2009) Curcumin disrupts the Mammalian target of rapamycin-raptor complex. Cancer Res 69(3):1000–1008PubMedGoogle Scholar
  15. Berchtold CM, Chen KS et al (2005) Perillyl alcohol inhibits a calcium-dependent constitutive nuclear factor-kappaB pathway. Cancer Res 65(18):8558–8566PubMedGoogle Scholar
  16. Berkel HJ, Turbat-Herrera EA et al (2001) Expression of the translation initiation factor eIF4E in the polyp-cancer sequence in the colon. Cancer Epidemiol Biomarkers Prev 10(6):663–666PubMedGoogle Scholar
  17. Bernstein J, Sella O et al (1997) PDGF2/c-sis mRNA leader contains a differentiation-linked internal ribosomal entry site (D-IRES). J Biol Chem 272(14):9356–9362PubMedGoogle Scholar
  18. Blagosklonny MV (2000) Cell death beyond apoptosis. Leukemia 14(8):1502–1508PubMedGoogle Scholar
  19. Bommareddy A, Hahm ER et al (2009) Atg5 regulates phenethyl isothiocyanate-induced autophagic and apoptotic cell death in human prostate cancer cells. Cancer Res 69(8):3704–3712PubMedGoogle Scholar
  20. Buechler RD, Peffley DM (2004) Proto oncogene/eukaryotic translation initiation factor (eIF) 4E attenuates mevalonate-mediated regulation of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase synthesis. Mol Carcinog 41(1):39–53PubMedGoogle Scholar
  21. Byrnes K, White S et al (2006) High eIF4E, VEGF, and microvessel density in stage I to III breast cancer. Ann Surg 243(5):684–690, discussion 691–682PubMedGoogle Scholar
  22. Cao Q, Richter JD (2002) Dissolution of the maskin-eIF4E complex by cytoplasmic polyadenylation and poly(A)-binding protein controls cyclin B1 mRNA translation and oocyte maturation. EMBO J 21(14):3852–3862PubMedGoogle Scholar
  23. Chen CN, Hsieh FJ et al (2004) Expression of eukaryotic initiation factor 4E in gastric adenocarcinoma and its association with clinical outcome. J Surg Oncol 86(1):22–27PubMedGoogle Scholar
  24. Chiu MI, Katz H et al (1994) RAPT1, a mammalian homolog of yeast Tor, interacts with the FKBP12/rapamycin complex. Proc Natl Acad Sci USA 91(26):12574–12578PubMedGoogle Scholar
  25. Choi JW, Peffley DM (1995) 3′-untranslated sequences mediate post-transcriptional regulation of 3-hydroxy-3-methylglutaryl-CoA reductase mRNA by 25-hydroxycholesterol. Biochem J 307(Pt 1):233–238PubMedGoogle Scholar
  26. Chung BH, Lee HY et al (2006) Perillyl alcohol inhibits the expression and function of the androgen receptor in human prostate cancer cells. Cancer Lett 236(2):222–228PubMedGoogle Scholar
  27. Clark SS (2006) Perillyl alcohol induces c-Myc-dependent apoptosis in Bcr/Abl-transformed leukemia cells. Oncology 70(1):13–18PubMedGoogle Scholar
  28. Clemens MJ, Bommer UA (1999) Translational control: the cancer connection. Int J Biochem Cell Biol 31(1):1–23PubMedGoogle Scholar
  29. Codogno P, Meijer AJ (2005) Autophagy and signaling: their role in cell survival and cell death. Cell Death Differ 12(Suppl 2):1509–1518PubMedGoogle Scholar
  30. Coleman PS, Chen LC et al (1997) Cholesterol metabolism and tumor cell proliferation. Subcell Biochem 28:363–435PubMedGoogle Scholar
  31. Constantinou A, Huberman E (1995) Genistein as an inducer of tumor cell differentiation: possible mechanisms of action. Proc Soc Exp Biol Med 208(1):109–115PubMedGoogle Scholar
  32. Corradetti MN, Guan KL (2006) Upstream of the mammalian target of rapamycin: do all roads pass through mTOR? Oncogene 25(48):6347–6360PubMedGoogle Scholar
  33. Corradetti MN, Inoki K et al (2004) Regulation of the TSC pathway by LKB1: evidence of a molecular link between tuberous sclerosis complex and Peutz-Jeghers syndrome. Genes Dev 18(13):1533–1538PubMedGoogle Scholar
  34. Correll CC, Edwards PA (1994) Mevalonic acid-dependent degradation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase in vivo and in vitro. J Biol Chem 269(1):633–638PubMedGoogle Scholar
  35. Correll CC, Ng L et al (1994) Identification of farnesol as the non-sterol derivative of mevalonic acid required for the accelerated degradation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase. J Biol Chem 269(26):17390–17393PubMedGoogle Scholar
  36. Crowell PL, Chang RR et al (1991) Selective inhibition of isoprenylation of 21-26-kDa proteins by the anticarcinogen d-limonene and its metabolites. J Biol Chem 266(26):17679–17685PubMedGoogle Scholar
  37. Davis JN, Singh B et al (1998) Genistein-induced upregulation of p21WAF1, downregulation of cyclin B, and induction of apoptosis in prostate cancer cells. Nutr Cancer 32(3):123–131PubMedGoogle Scholar
  38. Davis JN, Kucuk O et al (2001) Soy isoflavone supplementation in healthy men prevents NF-kappa B activation by TNF-alpha in blood lymphocytes. Free Radic Biol Med 30(11):1293–1302PubMedGoogle Scholar
  39. De Benedetti A, Graff JR (2004) eIF-4E expression and its role in malignancies and metastases. Oncogene 23(18):3189–3199PubMedGoogle Scholar
  40. De Gregorio E, Baron J et al (2001) Tethered-function analysis reveals that elF4E can recruit ribosomes independent of its binding to the cap structure. RNA 7(1):106–113PubMedGoogle Scholar
  41. DeBose-Boyd RA (2008) Feedback regulation of cholesterol synthesis: sterol-accelerated ubiquitination and degradation of HMG CoA reductase. Cell Res 18(6):609–621PubMedGoogle Scholar
  42. Defatta RJ, De Benedetti A (2003) Translational upregulation of yes accompanies eIF4E-mediated oncogenic transformation. Int J Oncol 23(6):1709–1713PubMedGoogle Scholar
  43. DeFatta RJ, Turbat-Herrera EA et al (1999) Elevated expression of eIF4E in confined early breast cancer lesions: possible role of hypoxia. Int J Cancer 80(4):516–522PubMedGoogle Scholar
  44. DeFatta RJ, Nathan CA et al (2000) Antisense RNA to eIF4E suppresses oncogenic properties of a head and neck squamous cell carcinoma cell line. Laryngoscope 110(6):928–933PubMedGoogle Scholar
  45. DeFatta RJ, Li Y et al (2002) Selective killing of cancer cells based on translational control of a suicide gene. Cancer Gene Ther 9(7):573–578PubMedGoogle Scholar
  46. Elson CE, Peffley DM et al (1999) Isoprenoid-mediated inhibition of mevalonate synthesis: potential application to cancer. Proc Soc Exp Biol Med 221(4):294–311PubMedGoogle Scholar
  47. Engstrom W, Schofield PN (1987) Expression of the 3-hydroxy-3-methylglutaryl coenzyme A-reductase and LDL-receptor genes in human embryonic tumours and in normal foetal tissues. Anticancer Res 7(3 Pt B):337–342PubMedGoogle Scholar
  48. Espel E (2005) The role of the AU-rich elements of mRNAs in controlling translation. Semin Cell Dev Biol 16(1):59–67PubMedGoogle Scholar
  49. Espenshade PJ, Hughes AL (2007) Regulation of sterol synthesis in eukaryotes. Annu Rev Genet 41:401–427PubMedGoogle Scholar
  50. Fernandez J, Yaman I et al (2001) Internal ribosome entry site-mediated translation of a mammalian mRNA is regulated by amino acid availability. J Biol Chem 276(15):12285–12291PubMedGoogle Scholar
  51. Fernandez J, Yaman I et al (2005) Ribosome stalling regulates IRES-mediated translation in eukaryotes, a parallel to prokaryotic attenuation. Mol Cell 17(3):405–416PubMedGoogle Scholar
  52. Fischer Jde S, Liao L et al (2010) Dynamic proteomic overview of glioblastoma cells (A172) exposed to perillyl alcohol. J Proteomics 73(5):1018–1027PubMedGoogle Scholar
  53. Forman HJ, Torres M et al (2002) Redox signaling. Mol Cell Biochem 234–235(1–2):49–62PubMedGoogle Scholar
  54. Fournier DB, Erdman JW Jr et al (1998) Soy, its components, and cancer prevention: a review of the in vitro, animal, and human data. Cancer Epidemiol Biomarkers Prev 7(11):1055–1065PubMedGoogle Scholar
  55. Fritz T, Buechler R, Peffley DM (1998) Translational efficiency of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase is regulated by 5′-untranslated (UTR) mRNA secondary structure. Circ Res 98:379Google Scholar
  56. Galluzzi L, Vicencio JM et al (2008) To die or not to die: that is the autophagic question. Curr Mol Med 8(2):78–91PubMedGoogle Scholar
  57. Gayen AK, Peffley DM (1995) The length of 5′-untranslated leader sequences influences distribution of 3-hydroxy-3-methylglutaryl-coenzyme A reductase mRNA in polysomes: effects of lovastatin, oxysterols, and mevalonate. Arch Biochem Biophys 322(2):475–485PubMedGoogle Scholar
  58. Ghosh PM, Ghosh-Choudhury N et al (1999) Role of RhoA activation in the growth and morphology of a murine prostate tumor cell line. Oncogene 18(28):4120–4130PubMedGoogle Scholar
  59. Gingras AC, Raught B et al (2001a) Control of translation by the target of rapamycin proteins. Prog Mol Subcell Biol 27:143–174PubMedGoogle Scholar
  60. Gingras AC, Raught B et al (2001b) Regulation of translation initiation by FRAP/mTOR. Genes Dev 15(7):807–826PubMedGoogle Scholar
  61. Giraud S, Greco A et al (2001) Translation initiation of the insulin-like growth factor I receptor mRNA is mediated by an internal ribosome entry site. J Biol Chem 276(8):5668–5675PubMedGoogle Scholar
  62. Goldson TM, Vielhauer G et al (2007) Eukaryotic initiation factor 4E variants alter the morphology, proliferation, and colony-formation properties of MDA-MB-435 cancer cells. Mol Carcinog 46(1):71–84PubMedGoogle Scholar
  63. Goldstein JL, Brown MS (1990) Regulation of the mevalonate pathway. Nature 343(6257):425–430PubMedGoogle Scholar
  64. Gould MN (1997) Cancer chemoprevention and therapy by monoterpenes. Environ Health Perspect 105(Suppl 4):977–979PubMedGoogle Scholar
  65. Graff JR, Zimmer SG (2003) Translational control and metastatic progression: enhanced activity of the mRNA cap-binding protein eIF-4E selectively enhances translation of metastasis-related mRNAs. Clin Exp Metastasis 20(3):265–273PubMedGoogle Scholar
  66. Graff JR, Konicek BW et al (2008) Targeting the eukaryotic translation initiation factor 4E for cancer therapy. Cancer Res 68(3):631–634PubMedGoogle Scholar
  67. Guilford JM, Pezzuto JM (2008) Natural products as inhibitors of carcinogenesis. Expert Opin Investig Drugs 17(9):1341–1352PubMedGoogle Scholar
  68. Gullett NP, Ruhul Amin AR et al (2010) Cancer prevention with natural compounds. Semin Oncol 37(3):258–281PubMedGoogle Scholar
  69. Halaby MJ, Yang DQ (2007) p53 translational control: a new facet of p53 regulation and its implication for tumorigenesis and cancer therapeutics. Gene 395(1–2):1–7PubMedGoogle Scholar
  70. Haluska P, Dy GK et al (2002) Farnesyl transferase inhibitors as anticancer agents. Eur J Cancer 38(13):1685–1700PubMedGoogle Scholar
  71. Handayani R, Rice L et al (2006) Soy isoflavones alter expression of genes associated with cancer progression, including interleukin-8, in androgen-independent PC-3 human prostate cancer cells. J Nutr 136(1):75–82PubMedGoogle Scholar
  72. Hekman M, Hamm H et al (2002) Associations of B- and C-Raf with cholesterol, phosphatidylserine, and lipid second messengers: preferential binding of Raf to artificial lipid rafts. J Biol Chem 277(27):24090–24102PubMedGoogle Scholar
  73. Henis-Korenblit S, Strumpf NL et al (2000) A novel form of DAP5 protein accumulates in apoptotic cells as a result of caspase cleavage and internal ribosome entry site-mediated translation. Mol Cell Biol 20(2):496–506PubMedGoogle Scholar
  74. Henis-Korenblit S, Shani G et al (2002) The caspase-cleaved DAP5 protein supports internal ribosome entry site-mediated translation of death proteins. Proc Natl Acad Sci USA 99(8):5400–5405PubMedGoogle Scholar
  75. Hentosh P, Yuh SH et al (2001) Sterol-independent regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase in tumor cells. Mol Carcinog 32(3):154–166PubMedGoogle Scholar
  76. Herbert TP, Fahraeus R et al (2000) Rapid induction of apoptosis mediated by peptides that bind initiation factor eIF4E. Curr Biol 10(13):793–796PubMedGoogle Scholar
  77. Herman-Antosiewicz A, Johnson DE et al (2006) Sulforaphane causes autophagy to inhibit release of cytochrome C and apoptosis in human prostate cancer cells. Cancer Res 66(11):5828–5835PubMedGoogle Scholar
  78. Hiipakka RA, Zhang HZ et al (2002) Structure-activity relationships for inhibition of human 5alpha-reductases by polyphenols. Biochem Pharmacol 63(6):1165–1176PubMedGoogle Scholar
  79. Holcik M, Gordon BW et al (2003) The internal ribosome entry site-mediated translation of antiapoptotic protein XIAP is modulated by the heterogeneous nuclear ribonucleoproteins C1 and C2. Mol Cell Biol 23(1):280–288PubMedGoogle Scholar
  80. Holz MK, Ballif BA et al (2005) mTOR and S6K1 mediate assembly of the translation preinitiation complex through dynamic protein interchange and ordered phosphorylation events. Cell 123(4):569–580PubMedGoogle Scholar
  81. Hsieh TC, Elangovan S et al (2010) Gamma-Tocotrienol controls proliferation, modulates expression of cell cycle regulatory proteins and up-regulates quinone reductase NQO2 in MCF-7 breast cancer cells. Anticancer Res 30(7):2869–2874PubMedGoogle Scholar
  82. Hu J, Straub J et al (2007) Phenethyl isothiocyanate, a cancer chemopreventive constituent of cruciferous vegetables, inhibits cap-dependent translation by regulating the level and phosphorylation of 4E-BP1. Cancer Res 67(8):3569–3573PubMedGoogle Scholar
  83. Huang M, Prendergast GC (2006) RhoB in cancer suppression. Histol Histopathol 21(2):213–218PubMedGoogle Scholar
  84. Huang J, Nasr M et al (1992) Genistein inhibits protein histidine kinase. J Biol Chem 267(22):15511–15515PubMedGoogle Scholar
  85. Hudes GR, Szarka CE et al (2000) Phase I pharmacokinetic trial of perillyl alcohol (NSC 641066) in patients with refractory solid malignancies. Clin Cancer Res 6(8):3071–3080PubMedGoogle Scholar
  86. Humar R, Kiefer FN et al (2002) Hypoxia enhances vascular cell proliferation and angiogenesis in vitro via rapamycin (mTOR)-dependent signaling. FASEB J 16(8):771–780PubMedGoogle Scholar
  87. Inoki K, Guan KL (2006) Complexity of the TOR signaling network. Trends Cell Biol 16(4):206–212PubMedGoogle Scholar
  88. Izquierdo JM, Cuezva JM (2000) Internal-ribosome-entry-site functional activity of the 3′-untranslated region of the mRNA for the beta subunit of mitochondrial H+−ATP synthase. Biochem J 346(Pt 3):849–855PubMedGoogle Scholar
  89. Jacinto E, Loewith R et al (2004) Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat Cell Biol 6(11):1122–1128PubMedGoogle Scholar
  90. Jeffrey IW, Bushell M et al (2002) Inhibition of protein synthesis in apoptosis: differential requirements by the tumor necrosis factor alpha family and a DNA-damaging agent for caspases and the double-stranded RNA-dependent protein kinase. Cancer Res 62(8):2272–2280PubMedGoogle Scholar
  91. Jo Y, Debose-Boyd RA (2010) Control of cholesterol synthesis through regulated ER-associated degradation of HMG CoA reductase. Crit Rev Biochem Mol Biol 45(3):185–198PubMedGoogle Scholar
  92. Jung CH, Ro SH et al (2010) mTOR regulation of autophagy. FEBS Lett 584(7):1287–1295PubMedGoogle Scholar
  93. Kevil C, Carter P et al (1995) Translational enhancement of FGF-2 by eIF-4 factors, and alternate utilization of CUG and AUG codons for translation initiation. Oncogene 11(11):2339–2348PubMedGoogle Scholar
  94. Khan N, Afaq F et al (2008) Cancer chemoprevention through dietary antioxidants: progress and promise. Antioxid Redox Signal 10(3):475–510PubMedGoogle Scholar
  95. Kim DH, Sarbassov DD et al (2003) GbetaL, a positive regulator of the rapamycin-sensitive pathway required for the nutrient-sensitive interaction between raptor and mTOR. Mol Cell 11(4):895–904PubMedGoogle Scholar
  96. Kim S, Sohn I et al (2005) Hepatic gene expression profiles are altered by genistein supplementation in mice with diet-induced obesity. J Nutr 135(1):33–41PubMedGoogle Scholar
  97. Kitanaka C, Kuchino Y (1999) Caspase-independent programmed cell death with necrotic morphology. Cell Death Differ 6(6):508–515PubMedGoogle Scholar
  98. Komarova AV, Brocard M et al (2006) The case for mRNA 5′ and 3′ end cross talk during translation in a eukaryotic cell. Prog Nucleic Acid Res Mol Biol 81:331–367PubMedGoogle Scholar
  99. Kozak M (2001a) Constraints on reinitiation of translation in mammals. Nucleic Acids Res 29(24):5226–5232PubMedGoogle Scholar
  100. Kozak M (2001b) New ways of initiating translation in eukaryotes? Mol Cell Biol 21(6):1899–1907PubMedGoogle Scholar
  101. Kozak M (2001c) A progress report on translational control in eukaryotes. Sci STKE 2001(71):PE1PubMedGoogle Scholar
  102. Kozak M (2005) Regulation of translation via mRNA structure in prokaryotes and eukaryotes. Gene 361:13–37PubMedGoogle Scholar
  103. Kozak M (2007) Lessons (not) learned from mistakes about translation. Gene 403(1–2):194–203PubMedGoogle Scholar
  104. Lawrence JC Jr, Abraham RT (1997) PHAS/4E-BPs as regulators of mRNA translation and cell proliferation. Trends Biochem Sci 22(9):345–349PubMedGoogle Scholar
  105. Lawrence JC Jr, Fadden P et al (1997) PHAS proteins as mediators of the actions of insulin, growth factors and cAMP on protein synthesis and cell proliferation. Adv Enzyme Regul 37:239–267PubMedGoogle Scholar
  106. Le Sourd F, Boulben S et al (2006) eEF1B: At the dawn of the 21st century. Biochim Biophys Acta 1759(1–2):13–31PubMedGoogle Scholar
  107. Lebowitz PF, Prendergast GC (1998) Functional interaction between RhoB and the transcription factor DB1. Cell Adhes Commun 6(4):277–287PubMedGoogle Scholar
  108. Lebowitz PF, Du W et al (1997) Prenylation of RhoB is required for its cell transforming function but not its ability to activate serum response element-dependent transcription. J Biol Chem 272(26):16093–16095PubMedGoogle Scholar
  109. Lee HK, Jeong S (2006) Beta-Catenin stabilizes cyclooxygenase-2 mRNA by interacting with AU-rich elements of 3′-UTR. Nucleic Acids Res 34(19):5705–5714PubMedGoogle Scholar
  110. Lee CH, Inoki K et al (2007) mTOR pathway as a target in tissue hypertrophy. Annu Rev Pharmacol Toxicol 47:443–467PubMedGoogle Scholar
  111. Lefranc F, Facchini V et al (2007) Proautophagic drugs: a novel means to combat apoptosis-resistant cancers, with a special emphasis on glioblastomas. Oncologist 12(12):1395–1403PubMedGoogle Scholar
  112. Levy S, Avni D et al (1991) Oligopyrimidine tract at the 5′ end of mammalian ribosomal protein mRNAs is required for their translational control. Proc Natl Acad Sci USA 88(8):3319–3323PubMedGoogle Scholar
  113. Li X, Marani M et al (2001) Overexpression of BCL-X(L) underlies the molecular basis for resistance to staurosporine-induced apoptosis in PC-3 cells. Cancer Res 61(4):1699–1706PubMedGoogle Scholar
  114. Li B, Gruner JS et al (2002) Prospective study of eukaryotic initiation factor 4E protein elevation and breast cancer outcome. Ann Surg 235(5):732–738; discussion 738–739PubMedGoogle Scholar
  115. Liao JK (2002) Isoprenoids as mediators of the biological effects of statins. J Clin Invest 110(3):285–288PubMedGoogle Scholar
  116. Lluria-Prevatt M, Morreale J et al (2002) Effects of perillyl alcohol on melanoma in the TPras mouse model. Cancer Epidemiol Biomarkers Prev 11(6):573–579PubMedGoogle Scholar
  117. Makela SI, Pylkkanen LH et al (1995) Dietary soybean may be antiestrogenic in male mice. J Nutr 125(3):437–445PubMedGoogle Scholar
  118. Mamane Y, Petroulakis E et al (2004) eIF4E–from translation to transformation. Oncogene 23(18):3172–3179PubMedGoogle Scholar
  119. Marissen WE, Gradi A et al (2000) Cleavage of eukaryotic translation initiation factor 4GII correlates with translation inhibition during apoptosis. Cell Death Differ 7(12):1234–1243PubMedGoogle Scholar
  120. Martinez O, Goud B (1998) Rab proteins. Biochim Biophys Acta 1404(1–2):101–112PubMedGoogle Scholar
  121. Matsukawa Y, Marui N et al (1993) Genistein arrests cell cycle progression at G2-M. Cancer Res 53(6):1328–1331PubMedGoogle Scholar
  122. McIntyre BS, Briski KP et al (2000) Antiproliferative and apoptotic effects of tocopherols and tocotrienols on normal mouse mammary epithelial cells. Lipids 35(2):171–180PubMedGoogle Scholar
  123. Mehta RG, Murillo G et al (2010) Cancer chemoprevention by natural products: how far have we come? Pharm Res 27(6):950–961PubMedGoogle Scholar
  124. Meigs TE, Simoni RD (1997) Farnesol as a regulator of HMG-CoA reductase degradation: characterization and role of farnesyl pyrophosphatase. Arch Biochem Biophys 345(1):1–9PubMedGoogle Scholar
  125. Meley D, Bauvy C et al (2006) AMP-activated protein kinase and the regulation of autophagic proteolysis. J Biol Chem 281(46):34870–34879PubMedGoogle Scholar
  126. Mo H, Elson CE (1999) Apoptosis and cell-cycle arrest in human and murine tumor cells are initiated by isoprenoids. J Nutr 129(4):804–813PubMedGoogle Scholar
  127. Mo H, Peffley DM, Elson CE (1999) Targeting the action of isoprenoids and related phytochemicals to tumors. In: Heber D, Blackburn GL, Go VLW (eds) Nutritional oncology. Academic, San Diego, pp 379–391Google Scholar
  128. Morley SJ, Coldwell MJ et al (2005) Initiation factor modifications in the preapoptotic phase. Cell Death Differ 12(6):571–584PubMedGoogle Scholar
  129. Nair S, Li W et al (2007) Natural dietary anti-cancer chemopreventive compounds: redox-mediated differential signaling mechanisms in cytoprotection of normal cells versus cytotoxicity in tumor cells. Acta Pharmacol Sin 28(4):459–472PubMedGoogle Scholar
  130. Nesaretnam K, Dorasamy S et al (2000) Tocotrienols inhibit growth of ZR-75-1 breast cancer cells. Int J Food Sci Nutr 51(Suppl):S95–S103PubMedGoogle Scholar
  131. Nevins TA, Harder ZM et al (2003) Distinct regulation of internal ribosome entry site-mediated translation following cellular stress is mediated by apoptotic fragments of eIF4G translation initiation factor family members eIF4GI and p97/DAP5/NAT1. J Biol Chem 278(6):3572–3579PubMedGoogle Scholar
  132. Nicklin P, Bergman P et al (2009) Bidirectional transport of amino acids regulates mTOR and autophagy. Cell 136(3):521–534PubMedGoogle Scholar
  133. Nobukuni T, Kozma SC et al (2007) hvps34, an ancient player, enters a growing game: mTOR Complex1/S6K1 signaling. Curr Opin Cell Biol 19(2):135–141PubMedGoogle Scholar
  134. Okura A, Arakawa H et al (1988) Effect of genistein on topoisomerase activity and on the growth of [Val 12] Ha-ras-transformed NIH 3T3 cells. Biochem Biophys Res Commun 157(1):183–189PubMedGoogle Scholar
  135. Origanti S, Shantz LM (2007) Ras transformation of RIE-1 cells activates cap-independent translation of ornithine decarboxylase: regulation by the Raf/MEK/ERK and phosphatidylinositol 3-kinase pathways. Cancer Res 67(10):4834–4842PubMedGoogle Scholar
  136. Pagliacci MC, Smacchia M et al (1994) Growth-inhibitory effects of the natural phyto-oestrogen genistein in MCF-7 human breast cancer cells. Eur J Cancer 30A(11):1675–1682PubMedGoogle Scholar
  137. Park SK, Sanders BG et al (2010) Tocotrienols induce apoptosis in breast cancer cell lines via an endoplasmic reticulum stress-dependent increase in extrinsic death receptor signaling. Breast Cancer Res Treat 124(2):361–375PubMedGoogle Scholar
  138. Peffley DM (1992) Regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase synthesis in Syrian hamster C100 cells by mevinolin, 25-hydroxycholesterol, and mevalonate: the role of posttranscriptional control. Somat Cell Mol Genet 18(1):19–32PubMedGoogle Scholar
  139. Peffley DM, Gayen AK (1997) Inhibition of squalene synthase but not squalene cyclase prevents mevalonate-mediated suppression of 3-hydroxy-3-methylglutaryl coenzyme A reductase synthesis at a posttranscriptional level. Arch Biochem Biophys 337(2):251–260PubMedGoogle Scholar
  140. Peffley DM, Gayen AK (2003) Plant-derived monoterpenes suppress hamster kidney cell 3-hydroxy-3-methylglutaryl coenzyme a reductase synthesis at the post-transcriptional level. J Nutr 133(1):38–44PubMedGoogle Scholar
  141. Peffley DM, Gayen AK et al (1998) Down-regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase mRNA levels and synthesis in syrian hamster C100 cells by the oxidosqualene cyclase inhibitor [4′-(6-allyl-ethyl-amino-hexyloxy)-2′-fluoro-phenyl]-(4-bromophenyl)-me thanone (Ro 48–8071): comparison to simvastatin. Biochem Pharmacol 56(4):439–449PubMedGoogle Scholar
  142. Peffley DM, Sharma C et al (2007) Perillyl alcohol and genistein differentially regulate PKB/Akt and 4E-BP1 phosphorylation as well as eIF4E/eIF4G interactions in human tumor cells. Arch Biochem Biophys 465(1):266–273PubMedGoogle Scholar
  143. Pelletier J, Brook JD et al (1991) Assignment of two of the translation initiation factor-4E (EIF4EL1 and EIF4EL2) genes to human chromosomes 4 and 20. Genomics 10(4):1079–1082PubMedGoogle Scholar
  144. Perkins CL, Fang G et al (2000) The role of Apaf-1, caspase-9, and bid proteins in etoposide- or paclitaxel-induced mitochondrial events during apoptosis. Cancer Res 60(6):1645–1653PubMedGoogle Scholar
  145. Petiot A, Ogier-Denis E et al (2000) Distinct classes of phosphatidylinositol 3′-kinases are involved in signaling pathways that control macroautophagy in HT-29 cells. J Biol Chem 275(2):992–998PubMedGoogle Scholar
  146. Piccinelli P, Samuelsson T (2007) Evolution of the iron-responsive element. RNA 13(7):952–966PubMedGoogle Scholar
  147. Pollard M, Luckert PH (1997) Influence of isoflavones in soy protein isolates on development of induced prostate-related cancers in L-W rats. Nutr Cancer 28(1):41–45PubMedGoogle Scholar
  148. Polunovsky VA, Gingras AC et al (2000) Translational control of the antiapoptotic function of Ras. J Biol Chem 275(32):24776–24780PubMedGoogle Scholar
  149. Poon RY, Toyoshima H et al (1995) Redistribution of the CDK inhibitor p27 between different cyclin.CDK complexes in the mouse fibroblast cell cycle and in cells arrested with lovastatin or ultraviolet irradiation. Mol Biol Cell 6(9):1197–1213PubMedGoogle Scholar
  150. Prendergast GC, Khosravi-Far R et al (1995) Critical role of Rho in cell transformation by oncogenic Ras. Oncogene 10(12):2289–2296PubMedGoogle Scholar
  151. Puissant A, Robert G et al (2010) Resveratrol promotes autophagic cell death in chronic myelogenous leukemia cells via JNK-mediated p62/SQSTM1 expression and AMPK activation. Cancer Res 70(3):1042–1052PubMedGoogle Scholar
  152. Pyronnet S, Pradayrol L et al (2000) A cell cycle-dependent internal ribosome entry site. Mol Cell 5(4):607–616PubMedGoogle Scholar
  153. Rabi T, Bishayee A (2009) Terpenoids and breast cancer chemoprevention. Breast Cancer Res Treat 115(2):223–239PubMedGoogle Scholar
  154. Ren Z, Elson CE et al (1997) Inhibition of type I and type II geranylgeranyl-protein transferases by the monoterpene perillyl alcohol in NIH3T3 cells. Biochem Pharmacol 54(1):113–120PubMedGoogle Scholar
  155. Reynolds GA, Goldstein JL et al (1985) Multiple mRNAs for 3-hydroxy-3-methylglutaryl coenzyme A reductase determined by multiple transcription initiation sites and intron splicing sites in the 5′-untranslated region. J Biol Chem 260(18):10369–10377PubMedGoogle Scholar
  156. Ripple GH, Gould MN et al (1998) Phase I clinical trial of perillyl alcohol administered daily. Clin Cancer Res 4(5):1159–1164PubMedGoogle Scholar
  157. Ripple GH, Gould MN et al (2000) Phase I clinical and pharmacokinetic study of perillyl alcohol administered four times a day. Clin Cancer Res 6(2):390–396PubMedGoogle Scholar
  158. Rubio I, Rodriguez-Viciana P et al (1997) Interaction of Ras with phosphoinositide 3-kinase gamma. Biochem J 326(Pt 3):891–895PubMedGoogle Scholar
  159. Salehi Z, Mashayekhi F (2006) Expression of the eukaryotic translation initiation factor 4E (eIF4E) and 4E-BP1 in esophageal cancer. Clin Biochem 39(4):404–409PubMedGoogle Scholar
  160. Sarbassov DD, Ali SM et al (2004) Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr Biol 14(14):1296–1302PubMedGoogle Scholar
  161. Sarbassov DD, Ali SM et al (2005) Growing roles for the mTOR pathway. Curr Opin Cell Biol 17(6):596–603PubMedGoogle Scholar
  162. Sarbassov DD, Ali SM et al (2006) Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol Cell 22(2):159–168PubMedGoogle Scholar
  163. Sato R (2010) Sterol metabolism and SREBP activation. Arch Biochem Biophys 501(2):177–181PubMedGoogle Scholar
  164. Schmidt EV (1999) The role of c-myc in cellular growth control. Oncogene 18(19):2988–2996PubMedGoogle Scholar
  165. Sehgal A, Briggs J et al (2000) The chicken c-Jun 5′ untranslated region directs translation by internal initiation. Oncogene 19(24):2836–2845PubMedGoogle Scholar
  166. Shantz LM (2004) Transcriptional and translational control of ornithine decarboxylase during Ras transformation. Biochem J 377(Pt 1):257–264PubMedGoogle Scholar
  167. Shaw RJ, Bardeesy N et al (2004) The LKB1 tumor suppressor negatively regulates mTOR signaling. Cancer Cell 6(1):91–99PubMedGoogle Scholar
  168. Shen JC, Klein RD et al (2000) Low-dose genistein induces cyclin-dependent kinase inhibitors and G(1) cell-cycle arrest in human prostate cancer cells. Mol Carcinog 29(2):92–102PubMedGoogle Scholar
  169. Sonenberg N (2008) eIF4E, the mRNA cap-binding protein: from basic discovery to translational research. Biochem Cell Biol 86(2):178–183PubMedGoogle Scholar
  170. Sonenberg N, Dever TE (2003) Eukaryotic translation initiation factors and regulators. Curr Opin Struct Biol 13(1):56–63PubMedGoogle Scholar
  171. Sonenberg N, Hinnebusch AG (2009) Regulation of translation initiation in eukaryotes: mechanisms and biological targets. Cell 136(4):731–745PubMedGoogle Scholar
  172. Spinozzi F, Pagliacci MC et al (1994) The natural tyrosine kinase inhibitor genistein produces cell cycle arrest and apoptosis in Jurkat T-leukemia cells. Leuk Res 18(6):431–439PubMedGoogle Scholar
  173. Stayrook KR, McKinzie JH et al (1998) Effects of the antitumor agent perillyl alcohol on H-Ras vs. K-Ras farnesylation and signal transduction in pancreatic cells. Anticancer Res 18(2A):823–828PubMedGoogle Scholar
  174. Stolovich M, Tang H et al (2002) Transduction of growth or mitogenic signals into translational activation of TOP mRNAs is fully reliant on the phosphatidylinositol 3-kinase-mediated pathway but requires neither S6K1 nor rpS6 phosphorylation. Mol Cell Biol 22(23):8101–8113PubMedGoogle Scholar
  175. Stratton SP, Alberts DS et al (2010) A phase 2a study of topical perillyl alcohol cream for chemoprevention of skin cancer. Cancer Prev Res (Phila) 3(2):160–169Google Scholar
  176. Subkhankulova T, Mitchell SA et al (2001) Internal ribosome entry segment-mediated initiation of c-Myc protein synthesis following genotoxic stress. Biochem J 359(Pt 1):183–192PubMedGoogle Scholar
  177. Suh Y, Afaq F et al (2010) Fisetin induces autophagic cell death through suppression of mTOR signaling pathway in prostate cancer cells. Carcinogenesis 31(8):1424–1433PubMedGoogle Scholar
  178. Sumitani S, Goya K et al (2002) Akt1 and Akt2 differently regulate muscle creatine kinase and myogenin gene transcription in insulin-induced differentiation of C2C12 myoblasts. Endocrinology 143(3):820–828PubMedGoogle Scholar
  179. Suzuki Y, Nakabayashi Y et al (2001) Ubiquitin-protein ligase activity of X-linked inhibitor of apoptosis protein promotes proteasomal degradation of caspase-3 and enhances its anti-apoptotic effect in Fas-induced cell death. Proc Natl Acad Sci USA 98(15):8662–8667PubMedGoogle Scholar
  180. Svitkin YV, Herdy B et al (2005) Eukaryotic translation initiation factor 4E availability controls the switch between cap-dependent and internal ribosomal entry site-mediated translation. Mol Cell Biol 25(23):10556–10565PubMedGoogle Scholar
  181. Tan A, Bitterman P et al (2000) Inhibition of Myc-dependent apoptosis by eukaryotic translation initiation factor 4E requires cyclin D1. Oncogene 19(11):1437–1447PubMedGoogle Scholar
  182. Teerink H, Voorma HO et al (1995) The human insulin-like growth factor II leader 1 contains an internal ribosomal entry site. Biochim Biophys Acta 1264(3):403–408PubMedGoogle Scholar
  183. Thornton S, Anand N et al (2003) Not just for housekeeping: protein initiation and elongation factors in cell growth and tumorigenesis. J Mol Med 81(9):536–548PubMedGoogle Scholar
  184. Trachootham D, Zhou Y et al (2006) Selective killing of oncogenically transformed cells through a ROS-mediated mechanism by beta-phenylethyl isothiocyanate. Cancer Cell 10(3):241–252PubMedGoogle Scholar
  185. van den Beucken T, Koritzinsky M et al (2006) Translational control of gene expression during hypoxia. Cancer Biol Ther 5(7):749–755PubMedGoogle Scholar
  186. Van Der Kelen K, Beyaert R et al (2009) Translational control of eukaryotic gene expression. Crit Rev Biochem Mol Biol 44(4):143–168Google Scholar
  187. van der Velden AW, Thomas AA (1999) The role of the 5′ untranslated region of an mRNA in translation regulation during development. Int J Biochem Cell Biol 31(1):87–106PubMedGoogle Scholar
  188. Vary TC, Goodman S et al (2005) Nutrient Regulation of PKC{epsilon} is Mediated by Leucine, not Insulin in Skeletal Muscle. Am J Physiol Endocrinol Metab 289(4):E684–E694PubMedGoogle Scholar
  189. von der Haar T, Gross JD et al (2004) The mRNA cap-binding protein eIF4E in post-transcriptional gene expression. Nat Struct Mol Biol 11(6):503–511PubMedGoogle Scholar
  190. Walker WA, Blackburn G (2004) Symposium introduction: nutrition and gene regulation. J Nutr 134(9):2434S–2436SPubMedGoogle Scholar
  191. Waskiewicz AJ, Johnson JC et al (1999) Phosphorylation of the cap-binding protein eukaryotic translation initiation factor 4E by protein kinase Mnk1 in vivo. Mol Cell Biol 19(3):1871–1880PubMedGoogle Scholar
  192. Wilkie GS, Dickson KS et al (2003) Regulation of mRNA translation by 5′- and 3′-UTR-binding factors. Trends Biochem Sci 28(4):182–188PubMedGoogle Scholar
  193. Wiseman DA, Werner SR et al (2007) Cell cycle arrest by the isoprenoids perillyl alcohol, geraniol, and farnesol is mediated by p21(Cip1) and p27(Kip1) in human pancreatic adenocarcinoma cells. J Pharmacol Exp Ther 320(3):1163–1170PubMedGoogle Scholar
  194. Wittke I, Madge B et al (2001) DAP-5 is involved in MycN/IFNgamma-induced apoptosis in human neuroblastoma cells. Cancer Lett 162(2):237–243PubMedGoogle Scholar
  195. Xu M, Floyd HS et al (2004) Perillyl alcohol-mediated inhibition of lung cancer cell line proliferation: potential mechanisms for its chemotherapeutic effects. Toxicol Appl Pharmacol 195(2):232–246PubMedGoogle Scholar
  196. Yan Y, Backer JM (2007) Regulation of class III (Vps34) PI3Ks. Biochem Soc Trans 35(Pt 2):239–241PubMedGoogle Scholar
  197. Yang L, Cao Z et al (2003) Coexistence of high levels of apoptotic signaling and inhibitor of apoptosis proteins in human tumor cells: implication for cancer specific therapy. Cancer Res 63(20):6815–6824PubMedGoogle Scholar
  198. Yeruva L, Pierre KJ et al (2007) Perillyl alcohol and perillic acid induced cell cycle arrest and apoptosis in non small cell lung cancer cells. Cancer Lett 257(2):216–226PubMedGoogle Scholar
  199. Yorimitsu T, Klionsky DJ (2005) Autophagy: molecular machinery for self-eating. Cell Death Differ 12(Suppl 2):1542–1552PubMedGoogle Scholar
  200. Yu W, Simmons-Menchaca M et al (1999) Induction of apoptosis in human breast cancer cells by tocopherols and tocotrienols. Nutr Cancer 33(1):26–32PubMedGoogle Scholar
  201. Yuri T, Danbara N et al (2004) Perillyl alcohol inhibits human breast cancer cell growth in vitro and in vivo. Breast Cancer Res Treat 84(3):251–260PubMedGoogle Scholar
  202. Zerial M, McBride H (2001) Rab proteins as membrane organizers. Nat Rev Mol Cell Biol 2(2):107–117PubMedGoogle Scholar
  203. Zhou JR, Gugger ET et al (1999) Soybean phytochemicals inhibit the growth of transplantable human prostate carcinoma and tumor angiogenesis in mice. J Nutr 129(9):1628–1635PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2012

Authors and Affiliations

  1. 1.Department of BiochemistryEdward Via College of Osteopathic MedicineSpartonburgUSA
  2. 2.Medical Laboratory and Radiation Sciences Department, College of Health SciencesOld Dominion UniversityNorfolkUSA

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