Hostname: page-component-586b7cd67f-tf8b9 Total loading time: 0 Render date: 2024-11-25T19:35:39.692Z Has data issue: false hasContentIssue false
  • English
  • Français

InTERTesting association between telomerase, mTOR and phytochemicals

Published online by Cambridge University Press:  29 March 2012

Tabetha Sundin  and
Patricia Hentosh
Tabetha Sundin
Affiliation:
Department of Biological Sciences, Old Dominion University, Norfolk, VA, USA
Patricia Hentosh*
Affiliation:
Department of Medical Laboratory and Radiation Sciences, Old Dominion University, Norfolk, VA, USA
*
*Corresponding author: Patricia Hentosh, Department of Medical Laboratory and Radiation Sciences, Old Dominion University, Norfolk, VA 23529, USA. E-mail: [email protected]
Get access Rights & Permissions [Opens in a new window]

Abstract

Telomeres are stretches of repeated DNA sequences located at the ends of chromosomes that are necessary to prevent loss of gene-coding DNA regions during replication. Telomerase – the enzyme responsible for immortalising cancer cells through the addition of telomeric repeats – is active in ~90% of human cancers. Telomerase activity is inhibited by various phytochemicals such as isoprenoids, genistein, curcumin, epigallocatechin-3-gallate, resveratrol and others. Human TERT (telomerase reverse transcriptase – the rate-limiting component of telomerase), heat shock protein 90, Akt, p70 S6 kinase (S6K) and mammalian target of rapamycin (mTOR) form a physical and functional complex with one another. The inclusion of Akt, mTOR and S6K in the TERT complex is compelling evidence to support mTOR-mediated control of telomerase activity. This review will define the role of mTOR, the master regulator of protein translation, in telomerase regulation and provide additional insights into the numerous ways in which telomerase activity is hindered by phytochemicals.

Type
Review Article
Information
Expert Reviews in Molecular Medicine , Volume 14 , March 2012 , e8
Copyright
Copyright © Cambridge University Press 2012

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

1Moyzis, R.K. et al. (1988) A highly conserved repetitive DNA sequence, (TTAGGG)n, present at the telomeres of human chromosomes. Proceedings of the National Academy of Sciences of the United States of America 85, 6622-6626CrossRefGoogle ScholarPubMed
2Blackburn, E.H. (2000) The end of the (DNA) line. Nature Structural Biology 7, 847-850CrossRefGoogle ScholarPubMed
3Vaziri, H. et al. (1994) Evidence for a mitotic clock in human hematopoietic stem cells: loss of telomeric DNA with age. Proceedings of the National Academy of Sciences of the United States of America 91, 9857-9860CrossRefGoogle ScholarPubMed
4Harley, C.B., Futcher, A.B. and Greider, C.W. (1990) Telomeres shorten during ageing of human fibroblasts. Nature 345, 458-460CrossRefGoogle ScholarPubMed
5Olovnikov, A.M. (1971) [Principle of marginotomy in template synthesis of polynucleotides]. Doklady Akademii Nauk SSSR 201, 1496-1499Google Scholar
6Watson, J.D. (1972) Origin of concatemeric T7 DNA. Nature. New Biology 239, 197-201Google Scholar
7de Lange, T. (2010) How shelterin solves the telomere end-protection problem. Cold Spring Harbor Symposia on Quantitative Biology 75, 167-177CrossRefGoogle ScholarPubMed
8Denchi, E.L. (2009) Give me a break: how telomeres suppress the DNA damage response. DNA Repair 8, 1118-1126CrossRefGoogle Scholar
9Huffman, K.E. et al. (2000) Telomere shortening is proportional to the size of the G-rich telomeric 3'-overhang. Journal of Biological Chemistry 275, 19719-19722CrossRefGoogle Scholar
10Kuilman, T. et al. (2010) The essence of senescence. Genes & Development 24, 2463-2479CrossRefGoogle ScholarPubMed
11Weinberg, R.A. (2007) The Biology of Cancer, Garland Science, New York, USAGoogle Scholar
12Shay, J.W. and Bacchetti, S. (1997) A survey of telomerase activity in human cancer. European Journal of Cancer 33, 787-791CrossRefGoogle ScholarPubMed
13Blackburn, E.H. (1992) Telomerases. Annual Review of Biochemistry 61, 113-129Google Scholar
14Greider, C.W. and Blackburn, E.H. (1987) The telomere terminal transferase of Tetrahymena is a ribonucleoprotein enzyme with two kinds of primer specificity. Cell 51, 887-898CrossRefGoogle ScholarPubMed
15Morin, G.B. (1989) The human telomere terminal transferase enzyme is a ribonucleoprotein that synthesizes TTAGGG repeats. Cell 59, 521-529CrossRefGoogle ScholarPubMed
16Nugent, C.I. and Lundblad, V. (1998) The telomerase reverse transcriptase: components and regulation. Genes & Development 12, 1073-1085Google Scholar
17Cairney, C.J. and Keith, W.N. (2008) Telomerase redefined: integrated regulation of hTR and hTERT for telomere maintenance and telomerase activity. Biochimie 90, 13-23CrossRefGoogle ScholarPubMed
18Lingner, J. et al. (1997) Reverse transcriptase motifs in the catalytic subunit of telomerase. Science 276, 561-567CrossRefGoogle ScholarPubMed
19Bodnar, A.G. et al. (1998) Extension of life-span by introduction of telomerase into normal human cells. Science 279, 349-352CrossRefGoogle ScholarPubMed
20Shay, J.W. et al. (2001) Telomerase and cancer. Human Molecular Genetics 10, 677-685Google Scholar
21Hiyama, E. et al. (1995) Correlating telomerase activity levels with human neuroblastoma outcomes. Nature Medicine 1, 249-255CrossRefGoogle ScholarPubMed
22Tsao, J. et al. (1997) Telomerase activity in normal and neoplastic breast. Clinical Cancer Research 3, 627-631Google Scholar
23Wright, W.E. et al. (1996) Telomerase activity in human germline and embryonic tissues and cells. Developmental Genetics 18, 173-1793.0.CO;2-3>CrossRefGoogle ScholarPubMed
24Shay, J.W. and Gazdar, A.F. (1997) Telomerase in the early detection of cancer. Journal of Clinical Pathology 50, 106-109CrossRefGoogle ScholarPubMed
25Kim, N.W. et al. (1994) Specific association of human telomerase activity with immortal cells and cancer. Science 266, 2011-2015Google Scholar
26Cesare, A.J. and Reddel, R.R. (2008) Telomere uncapping and alternative lengthening of telomeres. Mechanisms of Ageing and Development 129, 99-108CrossRefGoogle ScholarPubMed
27Artandi, S.E. et al. (2002) Constitutive telomerase expression promotes mammary carcinomas in aging mice. Proceedings of the National Academy of Sciences of the United States of America 99, 8191-8196CrossRefGoogle ScholarPubMed
28Gonzalez-Suarez, E. et al. (2001) Increased epidermal tumors and increased skin wound healing in transgenic mice overexpressing the catalytic subunit of telomerase, mTERT, in basal keratinocytes. EMBO Journal 20, 2619-2630CrossRefGoogle ScholarPubMed
29Vaziri, H. and Benchimol, S. (1998) Reconstitution of telomerase activity in normal human cells leads to elongation of telomeres and extended replicative life span. Current Biology 8, 279-282CrossRefGoogle ScholarPubMed
30Shay, J.W. and Keith, W.N. (2008) Targeting telomerase for cancer therapeutics. British Journal of Cancer 98, 677-683Google Scholar
31Orlando, C. et al. (2001) Telomerase in urological malignancy. Journal of Urology 166, 666-673Google Scholar
32Nakamura, T.M. et al. (1997) Telomerase catalytic subunit homologs from fission yeast and human. Science 277, 955-959CrossRefGoogle ScholarPubMed
33Kanaya, T. et al. (1998) hTERT is a critical determinant of telomerase activity in renal-cell carcinoma. International Journal of Cancer 78, 539-543Google Scholar
34Meyerson, M. et al. (1997) hEST2, the putative human telomerase catalytic subunit gene, is up-regulated in tumor cells and during immortalization. Cell 90, 785-795CrossRefGoogle ScholarPubMed
35Bilsland, A.E. et al. (2009) Dynamic telomerase gene suppression via network effects of GSK3 inhibition. PLoS One 4, e6459CrossRefGoogle ScholarPubMed
36Dong, C.K., Masutomi, K. and Hahn, W.C. (2005) Telomerase: regulation, function and transformation. Critical Reviews in Oncology/Hematology 54, 85-93CrossRefGoogle ScholarPubMed
37Greenberg, R.A. et al. (1999) Telomerase reverse transcriptase gene is a direct target of c-Myc but is not functionally equivalent in cellular transformation. Oncogene 18, 1219-1226Google Scholar
38Wang, J. et al. (1998) Myc activates telomerase. Genes & Development 12, 1769-1774CrossRefGoogle ScholarPubMed
39Wu, K.J. et al. (1999) Direct activation of TERT transcription by c-MYC. Nature Genetics 21, 220-224CrossRefGoogle ScholarPubMed
40Xu, D. et al. (2001) Switch from Myc/Max to Mad1/Max binding and decrease in histone acetylation at the telomerase reverse transcriptase promoter during differentiation of HL60 cells. Proceedings of the National Academy of Sciences of the United States of America 98, 3826-3831CrossRefGoogle ScholarPubMed
41Mai, W. et al. (2009) Deregulated GSK3{beta} sustains gastrointestinal cancer cells survival by modulating human telomerase reverse transcriptase and telomerase. Clinical Cancer Research: An Official Journal of the American Association for Cancer Research 15, 6810-6819CrossRefGoogle ScholarPubMed
42Nakatake, M. et al. (2007) STAT3 and PKC differentially regulate telomerase activity during megakaryocytic differentiation of K562 cells. Cell Cycle 6, 1496-1501CrossRefGoogle ScholarPubMed
43Ren, H. et al. (2010) Leptin upregulates telomerase activity and transcription of human telomerase reverse transcriptase in MCF-7 breast cancer cells. Biochemical and Biophysical Research Communications 394, 59-63Google Scholar
44Yatabe, N. et al. (2004) HIF-1-mediated activation of telomerase in cervical cancer cells. Oncogene 23, 3708-3715CrossRefGoogle ScholarPubMed
45Goueli, B.S. and Janknecht, R. (2004) Upregulation of the catalytic telomerase subunit by the transcription factor ER81 and oncogenic HER2/Neu, Ras, or Raf. Molecular Cell Biology 24, 25-35CrossRefGoogle ScholarPubMed
46Kanaya, T. et al. (2000) Adenoviral expression of p53 represses telomerase activity through down-regulation of human telomerase reverse transcriptase transcription. Clinical Cancer Research 6, 1239-1247Google ScholarPubMed
47Sun, B. et al. (2005) The minimal set of genetic alterations required for conversion of primary human fibroblasts to cancer cells in the subrenal capsule assay. Neoplasia 7, 585-593CrossRefGoogle ScholarPubMed
48Cong, Y.S., Wright, W.E. and Shay, J.W. (2002) Human telomerase and its regulation. Microbiology and Molecular Biology Reviews 66, 407-425Google Scholar
49Kang, S.S. et al. (1999) Akt protein kinase enhances human telomerase activity through phosphorylation of telomerase reverse transcriptase subunit. Journal of Biological Chemistry 274, 13085-13090CrossRefGoogle ScholarPubMed
50Sheng, W.Y., Chien, Y.L. and Wang, T.C. (2003) The dual role of protein kinase C in the regulation of telomerase activity in human lymphocytes. FEBS Letters 540, 91-95Google Scholar
51Liu, K., Hodes, R.J. and Weng, N. (2001) Cutting edge: telomerase activation in human T lymphocytes does not require increase in telomerase reverse transcriptase (hTERT) protein but is associated with hTERT phosphorylation and nuclear translocation. Journal of Immunology 166, 4826-4830Google Scholar
52Akiyama, M. et al. (2003) Nuclear factor-kappaB p65 mediates tumor necrosis factor alpha-induced nuclear translocation of telomerase reverse transcriptase protein. Cancer Research 63, 18-21Google ScholarPubMed
53Jagadeesh, S. and Banerjee, P.P. (2006) Inositol hexaphosphate represses telomerase activity and translocates TERT from the nucleus in mouse and human prostate cancer cells via the deactivation of Akt and PKCalpha. Biochemical and Biophysical Research Communications 349, 1361-1367CrossRefGoogle ScholarPubMed
54Seimiya, H. et al. (2000) Involvement of 14-3-3 proteins in nuclear localization of telomerase. EMBO Journal 19, 2652-2661CrossRefGoogle ScholarPubMed
55Kim, Y.W. et al. (2001) Protein kinase C modulates telomerase activity in human cervical cancer cells. Experimental Molecular Medicine 33, 156-163CrossRefGoogle ScholarPubMed
56Lin, Y. et al. (1998) Detection of telomerase activity in prostate needle-biopsy samples. Prostate 36, 121-1283.0.CO;2-L>CrossRefGoogle ScholarPubMed
57Janssens, V., Goris, J. and Van Hoof, C. (2005) PP2A: the expected tumor suppressor. Current Opinion in Genetics and Development 15, 34-41CrossRefGoogle ScholarPubMed
58Kawauchi, K., Ihjima, K. and Yamada, O. (2005) IL-2 increases human telomerase reverse transcriptase activity transcriptionally and posttranslationally through phosphatidylinositol 3'-kinase/Akt, heat shock protein 90, and mammalian target of rapamycin in transformed NK cells. Journal of Immunology 174, 5261-5269Google Scholar
59Woo, S.H. et al. (2009) A truncated form of p23 down-regulates telomerase activity via disruption of Hsp90 function. Journal of Biological Chemistry 284, 30871-30880CrossRefGoogle ScholarPubMed
60Kim, J.H. et al. (2005) Ubiquitin ligase MKRN1 modulates telomere length homeostasis through a proteolysis of hTERT. Genes & Development 19, 776-781CrossRefGoogle ScholarPubMed
61Salvatico, J. et al. (2010) Differentiation linked regulation of telomerase activity by Makorin-1. Molecular Cell Biochemistry 342, 241-250Google Scholar
62Sengupta, S., Peterson, T.R. and Sabatini, D.M. (2010) Regulation of the mTOR complex 1 pathway by nutrients, growth factors, and stress. Molecular Cell 40, 310-322CrossRefGoogle ScholarPubMed
63Jiang, B.H. and Liu, L.Z. (2008) Role of mTOR in anticancer drug resistance: perspectives for improved drug treatment. Drug Resistance Updates 11, 63-76Google Scholar
64Guertin, D.A. and Sabatini, D.M. (2007) Defining the role of mTOR in cancer. Cancer Cell 12, 9-22CrossRefGoogle ScholarPubMed
65Loewith, R. et al. (2002) Two TOR complexes, only one of which is rapamycin sensitive, have distinct roles in cell growth control. Molecular Cell 10, 457-468CrossRefGoogle ScholarPubMed
66Guertin, D.A. et al. (2006) Ablation in mice of the mTORC components raptor, rictor, or mLST8 reveals that mTORC2 is required for signaling to Akt-FOXO and PKCalpha, but not S6K1. Developmental Cell 11, 859-871CrossRefGoogle Scholar
67Sparks, C.A. and Guertin, D.A. (2010) Targeting mTOR: prospects for mTOR complex 2 inhibitors in cancer therapy. Oncogene 29, 3733-3744CrossRefGoogle ScholarPubMed
68Tee, A.R. et al. (2003) Tuberous sclerosis complex gene products, Tuberin and Hamartin, control mTOR signaling by acting as a GTPase-activating protein complex toward Rheb. Current Biology 13, 1259-1268Google Scholar
69Inoki, K. et al. (2002) TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nature Cell Biology 4, 648-657Google Scholar
70Li, Y. et al. (2003) The p38 and MK2 kinase cascade phosphorylates tuberin, the tuberous sclerosis 2 gene product, and enhances its interaction with 14-3-3. Journal of Biological Chemistry 278, 13663-13671CrossRefGoogle ScholarPubMed
71Potter, C.J., Pedraza, L.G. and Xu, T. (2002) Akt regulates growth by directly phosphorylating Tsc2. Nature Cell Biology 4, 658-665Google Scholar
72Rozen, F. et al. (1990) Bidirectional RNA helicase activity of eucaryotic translation initiation factors 4A and 4F. Molecular Cell Biology 10, 1134-1144Google ScholarPubMed
73Pestova, T.V. et al. (2001) Molecular mechanisms of translation initiation in eukaryotes. Proceedings of the National Academy of Sciences of the United States of America 98, 7029-7036CrossRefGoogle ScholarPubMed
74Pyronnet, S., Dostie, J. and Sonenberg, N. (2001) Suppression of cap-dependent translation in mitosis. Genes & Development 15, 2083-2093CrossRefGoogle ScholarPubMed
75Zemke, D., Azhar, S. and Majid, A. (2007) The mTOR pathway as a potential target for the development of therapies against neurological disease. Drug News & Perspectives 20, 495-499Google ScholarPubMed
76Rosenwald, I.B. et al. (1995) Eukaryotic translation initiation factor 4E regulates expression of cyclin D1 at transcriptional and post-transcriptional levels. Journal of Biological Chemistry 270, 21176-21180CrossRefGoogle ScholarPubMed
77Meyuhas, O. and Dreazen, A. (2009) Ribosomal protein S6 kinase from TOP mRNAs to cell size. Progress in Molecular Biology and Translational Science 90, 109-153CrossRefGoogle ScholarPubMed
78Vaira, V. et al. (2007) Regulation of survivin expression by IGF-1/mTOR signaling. Oncogene 26, 2678-2684CrossRefGoogle ScholarPubMed
79Riley, T. et al. (2008) Transcriptional control of human p53-regulated genes. Nature Reviews. Molecular Cell Biology 9, 402-412CrossRefGoogle ScholarPubMed
80Ghosh, S. et al. (2006) Essential role of tuberous sclerosis genes TSC1 and TSC2 in NF-kappaB activation and cell survival. Cancer Cell 10, 215-226Google Scholar
81Brugarolas, J. et al. (2004) Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex. Genes & Development 18, 2893-2904CrossRefGoogle ScholarPubMed
82Sofer, A. et al. (2005) Regulation of mTOR and cell growth in response to energy stress by REDD1. Molecular Cell Biology 25, 5834-5845CrossRefGoogle ScholarPubMed
83Nicklin, P. et al. (2009) Bidirectional transport of amino acids regulates mTOR and autophagy. Cell 136, 521-534CrossRefGoogle ScholarPubMed
84Liu, Q. et al. (2009) mTOR mediated anti-cancer drug discovery. Drug Discovery Today 6, 47-55Google ScholarPubMed
85Salmena, L., Carracedo, A. and Pandolfi, P.P. (2008) Tenets of PTEN tumor suppression. Cell 133, 403-414CrossRefGoogle ScholarPubMed
86Markman, B. et al. (2010) Status of PI3K inhibition and biomarker development in cancer therapeutics. Annals of Oncology 21, 683-691CrossRefGoogle ScholarPubMed
87Bellacosa, A. et al. (1995) Molecular alterations of the AKT2 oncogene in ovarian and breast carcinomas. International Journal of Cancer 64, 280-285CrossRefGoogle ScholarPubMed
88Carpten, J.D. et al. (2007) A transforming mutation in the pleckstrin homology domain of AKT1 in cancer. Nature 448, 439-444Google Scholar
89Staal, S.P. (1987) Molecular cloning of the akt oncogene and its human homologues AKT1 and AKT2: amplification of AKT1 in a primary human gastric adenocarcinoma. Proceedings of the National Academy of Sciences of the United States of America 84, 5034-5037Google Scholar
90Sorrells, D.L. et al. (1999) Competitive PCR to detect eIF4E gene amplification in head and neck cancer. Head & Neck 21, 60-65Google Scholar
91Nathan, C.O. et al. (1997) Detection of the proto-oncogene eIF4E in surgical margins may predict recurrence in head and neck cancer. Oncogene 15, 579-584CrossRefGoogle ScholarPubMed
92Vezina, C., Kudelski, A. and Sehgal, S.N. (1975) Rapamycin (AY-22 989), a new antifungal antibiotic. I. Taxonomy of the producing streptomycete and isolation of the active principle. Journal of Antibiotics 28, 721-726CrossRefGoogle ScholarPubMed
93Jacinto, E. et al. (2004) Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nature Cell Biology 6, 1122-1128Google Scholar
94Oshiro, N. et al. (2004) Dissociation of raptor from mTOR is a mechanism of rapamycin-induced inhibition of mTOR function. Genes to Cells: Devoted to Molecular & Cellular Mechanisms 9, 359-366Google Scholar
95Soliman, G.A. et al. (2010) mTOR Ser-2481 autophosphorylation monitors mTORC-specific catalytic activity and clarifies rapamycin mechanism of action. Journal of Biological Chemistry 285, 7866-7879CrossRefGoogle ScholarPubMed
96Chan, S. (2004) Targeting the mammalian target of rapamycin (mTOR): a new approach to treating cancer. British Journal of Cancer 91, 1420-1424Google Scholar
97Jimeno, A. et al. (2008) Pharmacodynamic-guided modified continuous reassessment method-based, dose-finding study of rapamycin in adult patients with solid tumors. Journal of Clinical Oncology 26, 4172-4179CrossRefGoogle ScholarPubMed
98Buechler, R.D. and Peffley, D.M. (2004) Proto oncogene/eukaryotic translation initiation factor (eIF) 4E attenuates mevalonate-mediated regulation of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase synthesis. Molecular Carcinogenesis 41, 39-53Google Scholar
99Peffley, D.M. et al. (2007) Perillyl alcohol and genistein differentially regulate PKB/Akt and 4E-BP1 phosphorylation as well as eIF4E/eIF4 G interactions in human tumor cells. Archives of Biochemistry and Biophysics 465, 266-273CrossRefGoogle Scholar
100Zhao, Y.M. et al. (2008) Antiproliferative effect of rapamycin on human T-cell leukemia cell line Jurkat by cell cycle arrest and telomerase inhibition. Acta Pharmacologica Sinica 29, 481-488Google Scholar
101Zhou, C. et al. (2003) Rapamycin inhibits telomerase activity by decreasing the hTERT mRNA level in endometrial cancer cells. Molecular Cancer Therapy 2, 789-795Google ScholarPubMed
102Bu, X. et al. (2007) Coupled down-regulation of mTOR and telomerase activity during fluorouracil-induced apoptosis of hepatocarcinoma cells. BMC Cancer 7, 208Google Scholar
103Sabatini, D.M. et al. (1994) RAFT1: a mammalian protein that binds to FKBP12 in a rapamycin-dependent fashion and is homologous to yeast TORs. Cell 78, 35-43Google Scholar
104Hara, K. et al. (2002) Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action. Cell 110, 177-189Google Scholar
105Nojima, H. et al. (2003) The mammalian target of rapamycin (mTOR) partner, raptor, binds the mTOR substrates p70 S6 kinase and 4E-BP1 through their TOR signaling (TOS) motif. Journal of Biological Chemistry 278, 15461-15464Google Scholar
106Delgoffe, G.M. et al. (2009) Enhanced interaction between Hsp90 and raptor regulates mTOR signaling upon T cell activation. Molecular Immunology 46, 2694-2698Google Scholar
107Ohji, G. et al. (2006) Suppression of the mTOR-raptor signaling pathway by the inhibitor of heat shock protein 90 geldanamycin. Journal of Biochemistry 139, 129-135CrossRefGoogle ScholarPubMed
108Sato, S., Fujita, N. and Tsuruo, T. (2000) Modulation of Akt kinase activity by binding to Hsp90. Proceedings of the National Academy of Sciences of the United States of America 97, 10832-10837Google Scholar
109Forsythe, H.L. et al. (2001) Stable association of hsp90 and p23, but Not hsp70, with active human telomerase. Journal of Biological Chemistry 276, 15571-15574Google Scholar
110Haendeler, J. et al. (2003) Hydrogen peroxide triggers nuclear export of telomerase reverse transcriptase via Src kinase family-dependent phosphorylation of tyrosine 707. Molecular Cell Biology 23, 4598-4610Google Scholar
111Makhnevych, T. and Houry, W.A. (2011) The role of Hsp90 in protein complex assembly. Biochimica et Biophysica Acta 1823, 674-82Google Scholar
112Czerninski, R. et al. (2009) Targeting mammalian target of rapamycin by rapamycin prevents tumor progression in an oral-specific chemical carcinogenesis model. Cancer Prevention Research (Philadelphia) 2, 27-36CrossRefGoogle Scholar
113Wei, C. et al. (2009) Chemopreventive efficacy of rapamycin on Peutz-Jeghers syndrome in a mouse model. Cancer Letters 277, 149-154Google Scholar
114Dennis, P.A. (2009) Rapamycin for chemoprevention of upper aerodigestive tract cancers. Cancer Prevention Research (Philadelphia) 2, 7-9Google Scholar
115Wong, K.K. (2009) Oral-specific chemical carcinogenesis in mice: an exciting model for cancer prevention and therapy. Cancer Prevention Research (Philadelphia) 2, 10-13CrossRefGoogle ScholarPubMed
116Elson, C.E. et al. (1999) Isoprenoid-mediated inhibition of mevalonate synthesis: potential application to cancer. Proceedings of the Society for Experimental Biological Medicine 221, 294-311Google Scholar
117Gershenzon, J. and Dudareva, N. (2007) The function of terpene natural products in the natural world. Nature Chemical Biology 3, 408-414Google Scholar
118Kirby, J. and Keasling, J.D. (2009) Biosynthesis of plant isoprenoids: perspectives for microbial engineering. Annual Review of Plant Biology 60, 335-355CrossRefGoogle ScholarPubMed
119Pan, M.H. and Ho, C.T. (2008) Chemopreventive effects of natural dietary compounds on cancer development. Chemical Society Reviews 37, 2558-2574Google Scholar
120Rabi, T. and Bishayee, A. (2009) Terpenoids and breast cancer chemoprevention. Breast Cancer Research Treatment 115, 223-239Google Scholar
121Yang, H. and Dou, Q.P. (2010) Targeting apoptosis pathway with natural terpenoids: implications for treatment of breast and prostate cancer. Current Drug Targets 11, 733-744Google Scholar
122Bettuzzi, S. et al. (2006) Chemoprevention of human prostate cancer by oral administration of green tea catechins in volunteers with high-grade prostate intraepithelial neoplasia: a preliminary report from a one-year proof-of-principle study. Cancer Research 66, 1234-1240Google Scholar
123Zou, C. et al. (2010) Green tea compound in chemoprevention of cervical cancer. International Journal of Gynecological Cancer: Official Journal of the International Gynecological Cancer Society 20, 617-624Google Scholar
124Fuggetta, M.P. et al. (2006) Effect of resveratrol on proliferation and telomerase activity of human colon cancer cells in vitro. Journal of Experimental & Clinical Cancer Research: CR 25, 189-193Google Scholar
125Jahangir, T. and Sultana, S. (2007) Perillyl alcohol protects against Fe-NTA-induced nephrotoxicity and early tumor promotional events in rat experimental model. Evidence-based Complement Alternative Medicine 4, 439-445CrossRefGoogle ScholarPubMed
126Liston, B.W. et al. (2003) Perillyl alcohol as a chemopreventive agent in N-nitrosomethylbenzylamine-induced rat esophageal tumorigenesis. Cancer Research 63, 2399-2403Google Scholar
127Giovannucci, E. et al. (2002) A prospective study of tomato products, lycopene, and prostate cancer risk. Journal of National Cancer Institute 94, 391-398Google Scholar
128Schwarz, S. et al. (2008) Lycopene inhibits disease progression in patients with benign prostate hyperplasia. Journal of Nutrition 138, 49-53Google Scholar
129Tang, F.Y. et al. (2009) Concomitant supplementation of lycopene and eicosapentaenoic acid inhibits the proliferation of human colon cancer cells. Journal of Nutritional Biochemistry 20, 426-434Google Scholar
130Khan, N. et al. (2011) Dual inhibition of PI3K/AKT and mTOR signaling in human non-small cell lung cancer cells by a dietary flavonoid fisetin. International Journal of Cancer 130, 1695-705Google Scholar
131Beevers, C.S. et al. (2009) Curcumin disrupts the Mammalian target of rapamycin-raptor complex. Cancer Research 69, 1000-1008CrossRefGoogle ScholarPubMed
132Chakravarti, N. et al. (2010) Differential inhibition of protein translation machinery by curcumin in normal, immortalized, and malignant oral epithelial cells. Cancer Prevention Research (Philadelphia) 3, 331-338Google Scholar
133Mukherjee Nee Chakraborty, S. et al. (2007) Curcumin-induced apoptosis in human leukemia cell HL-60 is associated with inhibition of telomerase activity. Molecular Cell Biochemistry 297, 31-39Google Scholar
134Singh, M. and Singh, N. (2009) Molecular mechanism of curcumin induced cytotoxicity in human cervical carcinoma cells. Molecular Cell Biology 325, 107-119Google Scholar
135Lee, J.H. and Chung, I.K. (2010) Curcumin inhibits nuclear localization of telomerase by dissociating the Hsp90 co-chaperone p23 from hTERT. Cancer Letters 290, 76-86Google Scholar
136Lanzilli, G. et al. (2006) Resveratrol down-regulates the growth and telomerase activity of breast cancer cells in vitro. International Journal of Oncology 28, 641-648Google ScholarPubMed
137Jagadeesh, S., Kyo, S. and Banerjee, P.P. (2006) Genistein represses telomerase activity via both transcriptional and posttranslational mechanisms in human prostate cancer cells. Cancer Research 66, 2107-2115CrossRefGoogle ScholarPubMed
138Ouchi, H. et al. (2005) Genistein induces cell growth inhibition in prostate cancer through the suppression of telomerase activity. International Journal of Urology: Official Journal of the Japanese Urological Association 12, 73-80Google Scholar
139Wang, X. et al. (2009) Apoptosis induction effects of EGCG in laryngeal squamous cell carcinoma cells through telomerase repression. Archives of Pharmacalogical Research 32, 1263-1269Google Scholar
140Thelen, P. et al. (2005) Tectorigenin and other phytochemicals extracted from leopard lily Belamcanda chinensis affect new and established targets for therapies in prostate cancer. Carcinogenesis 26, 1360-1367Google Scholar
141Murtaza, I. et al. (2009) Fisetin, a natural flavonoid, targets chemoresistant human pancreatic cancer AsPC-1 cells through DR3-mediated inhibition of NF-kappaB. International Journal of Cancer 125, 2465-2473Google Scholar
142Shin, S. et al. (2011) Glycogen synthase kinase (GSK)-3 promotes p70 ribosomal protein S6 kinase (p70S6K) activity and cell proliferation. Proceedings of the National Academy of Sciences of the United States of America 108, E1204-E1213Google Scholar