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Nutrient Signaling – Protein Kinase to Transcriptional Activation

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Bioactive Compounds and Cancer

Part of the book series: Nutrition and Health ((NH))

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Key Points

1. The widespread opinion today is that cancer may be prevented or treated by targeting specific cancer genes, signaling proteins, and transcription factors. Transcriptions factors are comprised of one or more proteins that bind to a specific DNA gene sequence and act to initiate transcription.

2. The molecular mechanisms explaining how normal cells undergo transformation to cancer cells induced by tumor promoters have been the subject of intense investigation. These studies have revealed that the mitogen-activated protein (MAP) kinase signaling pathways are activated differentially by various tumor promoters.

3. The activation of transcription factors including AP-1, NF-κB, p53, NFAT, and CREB protein results in transcription of genes whose proteins regulate a multitude of cellular responses including apoptosis, proliferation, inflammation, differentiation, and development.

4. Nutrients and dietary factors have attracted a great deal of interest because of their perceived ability to act as highly effective chemopreventive agents by targeting protein kinases and/or transcription factors, with very few adverse side effects.

5. The AP-1 transcription factor is a potential target mediated by upstream kinase cascades for regulation and chemoprevention by specific nutrients, including epigallocatechin gallate (EGCG), theaflavins, caffeine, [6]-gingerol, resveratrol, and various flavonols such as kaempferol, quercetin, and myricetin.

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References

  1. Darnell, J.E., Jr. (2002) Transcription factors as targets for cancer therapy. Nat Rev Cancer 2, 740–49.

    Article  PubMed  CAS  Google Scholar 

  2. Hong, W.K. (2003) General keynote: The impact of cancer chemoprevention. Gynecol Oncol 88, S56–S58.

    Article  PubMed  Google Scholar 

  3. Bode, A.M., and Dong, Z. (2003) Mitogen-Activated Protein Kinase Activation in UV-Induced Signal Transduction. Sci STKE 2003, re2.

    Article  PubMed  Google Scholar 

  4. Bode, A.M., and Dong, Z. (2004) Post-translational modification of p53 in tumorigenesis. Nat Rev Cancer 4, 793–805.

    Article  PubMed  CAS  Google Scholar 

  5. Bode, A.M., and Dong, Z. (2005) Signal transduction pathways in cancer development and as targets for cancer prevention. Prog Nucleic Acid Res Mol Biol 79, 237–97.

    Article  PubMed  CAS  Google Scholar 

  6. Bode, A.M., and Dong, Z. (2005) Inducible covalent posttranslational modification of histone H3. Sci STKE 2005, re4.

    Article  PubMed  Google Scholar 

  7. Bode, A.M., and Dong, Z. (2006) Molecular and cellular targets. Mol Carcinog 45, 422–30.

    Article  PubMed  CAS  Google Scholar 

  8. Bode, A.M., and Dong, Z. (2007) The functional contrariety of JNK. Mol Carcinog 46, 591–98.

    Article  PubMed  CAS  Google Scholar 

  9. Wu, W.S., Wu, J.R., and Hu, C.T. (2008) Signal cross talks for sustained MAPK activation and cell migration: The potential role of reactive oxygen species. Cancer Metastasis Rev 27, 303–14.

    Article  PubMed  CAS  Google Scholar 

  10. Friday, B.B., and Adjei, A.A. (2008) Advances in targeting the Ras/Raf/MEK/Erk mitogen-activated protein kinase cascade with MEK inhibitors for cancer therapy. Clin Cancer Res 14, 342–46.

    Article  PubMed  CAS  Google Scholar 

  11. Fecher, L.A., Amaravadi, R.K., and Flaherty, K.T. (2008) The MAPK pathway in melanoma. Current Opin Oncol 20, 183–89.

    Article  CAS  Google Scholar 

  12. Treisman, R. (1996) Regulation of transcription by MAP kinase cascades. Curr Opin Cell Biol 8, 205–15.

    Article  PubMed  CAS  Google Scholar 

  13. Hazzalin, C.A., and Mahadevan, L.C. (2002) MAPK-regulated transcription: A continuously variable gene switch? Nat Rev Mol Cell Biol 3, 30–40.

    Article  PubMed  CAS  Google Scholar 

  14. Pearson, G., Robinson, F., Beers Gibson, T., Xu, B.E., Karandikar, M., Berman, K., and Cobb, M.H. (2001) Mitogen-activated protein (MAP) kinase pathways: Regulation and physiological functions. Endocr Rev 22, 153–83.

    Article  PubMed  CAS  Google Scholar 

  15. Schaeffer, H.J., and Weber, M.J. (1999) Mitogen-activated protein kinases: Specific messages from ubiquitous messengers. Mol Cell Biol 19, 2435–44.

    PubMed  CAS  Google Scholar 

  16. Cho, Y.Y., Bode, A.M., Mizuno, H., Choi, B.Y., Choi, H.S., and Dong, Z. (2004) A novel role for mixed-lineage kinase-like mitogen-activated protein triple kinase alpha in neoplastic cell transformation and tumor development. Cancer Res 64, 3855–64.

    Article  PubMed  CAS  Google Scholar 

  17. Cowley, S., Paterson, H., Kemp, P., and Marshall, C.J. (1994) Activation of MAP kinase kinase is necessary and sufficient for PC12 differentiation and for transformation of NIH 3T3 cells. Cell 77, 841–52.

    Article  PubMed  CAS  Google Scholar 

  18. Kallunki, T., Su, B., Tsigelny, I., Sluss, H.K., Derijard, B., Moore, G., Davis, R., and Karin, M. (1994) JNK2 contains a specificity-determining region responsible for efficient c-Jun binding and phosphorylation. Genes Dev 8, 2996–3007.

    Article  PubMed  CAS  Google Scholar 

  19. Huang, C., Ma, W.Y., Li, J., and Dong, Z. (1999) Arsenic induces apoptosis through a c-Jun NH2-terminal kinase-dependent, p53-independent pathway. Cancer Res 59, 3053–58.

    PubMed  CAS  Google Scholar 

  20. Bode, A.M., and Dong, Z. (2000) Apoptosis induction by arsenic: Mechanisms of actions and possible clinical applications for treating therapy-resistant cancers. Drug Resist Updat 3, 21–29.

    Article  PubMed  CAS  Google Scholar 

  21. Bode, A.M., and Dong, Z. (2002) The paradox of arsenic: Molecular mechanisms of cell transformation and chemotherapeutic effects. Crit Rev Oncol Hematol 42, 5–24.

    Article  PubMed  Google Scholar 

  22. Bode, A.M., and Dong, Z. (2004) Targeting signal transduction pathways by chemopreventive agents. Mutat Res 555, 33–51.

    Article  PubMed  CAS  Google Scholar 

  23. Lu, H., and Huan, C. (2007) Transcription factor NFAT, its role in cancer development, and as a potential target for chemoprevention. Curr Cancer Drug Targets 7, 343–53.

    Article  PubMed  CAS  Google Scholar 

  24. Medyouf, H., and Ghysdael, J. (2008) The calcineurin/NFAT signaling pathway: A novel therapeutic target in leukemia and solid tumors. Cell Cycle 7, 297–303.

    Article  PubMed  CAS  Google Scholar 

  25. Siu, Y.T., and Jin, D.Y. (2007) CREB–a real culprit in oncogenesis. FEBS J 274, 3224–32.

    Article  PubMed  CAS  Google Scholar 

  26. Angel, P., and Karin, M. (1991) The role of Jun, Fos and the AP-1 complex in cell-proliferation and transformation. Biochim Biophys Acta 1072, 129–57.

    PubMed  CAS  Google Scholar 

  27. Eferl, R., and Wagner, E.F. (2003) AP-1: A double-edged sword in tumorigenesis. Nat Rev Cancer 3, 859–68.

    Article  PubMed  CAS  Google Scholar 

  28. Barthelman, M., Chen, W., Gensler, H.L., Huang, C., Dong, Z., and Bowden, G.T. (1998) Inhibitory effects of perillyl alcohol on UVB-induced murine skin cancer and AP-1 transactivation. Cancer Res 58, 711–16.

    PubMed  CAS  Google Scholar 

  29. Dong, Z., Birrer, M.J., Watts, R.G., Matrisian, L.M., and Colburn, N.H. (1994) Blocking of tumor promoter-induced AP-1 activity inhibits induced transformation in JB6 mouse epidermal cells. Proc Natl Acad Sci U S A 91, 609–13.

    Article  PubMed  CAS  Google Scholar 

  30. Dong, Z., Watts, S.G., Sun, Y., and Colburn, N.H. (1995) Progressive elevation of AP-1 activity during preneoplastic-to neoplastic progression as modeled in mouse JB6 cell variants. Int J Oncol 7, 359–64.

    PubMed  CAS  Google Scholar 

  31. Matthews, C.P., Colburn, N.H., and Young, M.R. (2007) AP-1 a target for cancer prevention. Curr Cancer Drug Targets 7, 317–24.

    Article  PubMed  CAS  Google Scholar 

  32. Ozanne, B.W., Spence, H.J., McGarry, L.C., and Hennigan, R.F. (2007) Transcription factors control invasion: AP-1 the first among equals. Oncogene 26, 1–10.

    Article  PubMed  CAS  Google Scholar 

  33. Verde, P., Casalino, L., Talotta, F., Yaniv, M., and Weitzman, J.B. (2007) Deciphering AP-1 function in tumorigenesis: Fra-ternizing on target promoters. Cell Cycle 6, 2633–39.

    Article  PubMed  CAS  Google Scholar 

  34. Dong, Z., Crawford, H.C., Lavrovsky, V., Taub, D., Watts, R., Matrisian, L.M., and Colburn, N.H. (1997) A dominant negative mutant of jun blocking 12-O-tetradecanoylphorbol-13- acetate-induced invasion in mouse keratinocytes. Mol Carcinog 19, 204–12.

    Article  PubMed  CAS  Google Scholar 

  35. Huang, C., Ma, W.-Y., and Dong, Z. (1996) Inhibitory effects of ascorbic acid on AP-1 activity and transformation of JB6 cells. Int J Oncol 8, 389–93.

    PubMed  CAS  Google Scholar 

  36. Huang, C., Ma, W.Y., Dawson, M.I., Rincon, M., Flavell, R.A., and Dong, Z. (1997) Blocking activator protein-1 activity, but not activating retinoic acid response element, is required for the antitumor promotion effect of retinoic acid. Proc Natl Acad Sci U S A 94, 5826–30.

    Article  PubMed  CAS  Google Scholar 

  37. Li, J.J., Dong, Z., Dawson, M.I., and Colburn, N.H. (1996) Inhibition of tumor promoter-induced transformation by retinoids that transrepress AP-1 without transactivating retinoic acid response element. Cancer Res 56, 483–89.

    PubMed  CAS  Google Scholar 

  38. Domann, F.E., Jr., Levy, J.P., Finch, J.S., and Bowden, G.T. (1994) Constitutive AP-1 DNA binding and transactivating ability of malignant but not benign mouse epidermal cells. Mol Carcinog 9, 61–66.

    Article  PubMed  CAS  Google Scholar 

  39. Chen, D., Milacic, V., Chen, M.S., Wan, S.B., Lam, W.H., Huo, C., Landis-Piwowar, K.R., Cui, Q.C., Wali, A., Chan, T.H., and Dou, Q.P. (2008) Tea polyphenols, their biological effects and potential molecular targets. Histol Histopathol 23, 487–96.

    PubMed  Google Scholar 

  40. Ikeda, I. (2008) Multifunctional effects of green tea catechins on prevention of the metabolic syndrome. Asia Pacific J Clini Nutr 17(Suppl 1), 273–4.

    CAS  Google Scholar 

  41. Kim, J.A. (2008) Mechanisms underlying beneficial health effects of tea catechins to improve insulin resistance and endothelial dysfunction. Endocrine Metab Immune Disord Drug Targets 8, 82–88.

    Article  CAS  Google Scholar 

  42. Na, H.K., and Surh, Y.J. (2008) Modulation of Nrf2-mediated antioxidant and detoxifying enzyme induction by the green tea polyphenol EGCG. Food Chem Toxicol 46, 1271–78.

    Article  PubMed  CAS  Google Scholar 

  43. Shankar, S., Ganapathy, S., and Srivastava, R.K. (2007) Green tea polyphenols: Biology and therapeutic implications in cancer. Front Biosci 12, 4881–99.

    Article  PubMed  CAS  Google Scholar 

  44. Chen, L., and Zhang, H.Y. (2007) Cancer preventive mechanisms of the green tea polyphenol (-)-epigallocatechin-3-gallate. Molecules 12, 946–57.

    Article  PubMed  CAS  Google Scholar 

  45. Ju, J., Lu, G., Lambert, J.D., and Yang, C.S. (2007) Inhibition of carcinogenesis by tea constituents. Semin Cancer Biol 17, 395–402.

    Article  PubMed  CAS  Google Scholar 

  46. Yang, C.S., Lambert, J.D., Ju, J., Lu, G., and Sang, S. (2007) Tea and cancer prevention: Molecular mechanisms and human relevance. Toxicol Appl Pharmacol 224, 265–73.

    Article  PubMed  CAS  Google Scholar 

  47. Bode, A.M., and Dong, Z. (2007) The enigmatic effects of caffeine in cell cycle and cancer. Cancer Lett 247, 26–39.

    Article  PubMed  CAS  Google Scholar 

  48. Aggarwal, B.B., Kunnumakkara, A.B., Harikumar, K.B., Tharakan, S.T., Sung, B., and Anand, P. (2008) Potential of Spice-Derived Phytochemicals for Cancer Prevention. Planta Medica 74(13), 1560–69.

    Article  PubMed  CAS  Google Scholar 

  49. Bode, A.M., and Dong, Z., eds. (2004) Ginger. New York: Marcel Dekker.

    Google Scholar 

  50. Zhao, L., and Brinton, R.D. (2007) WHI and WHIMS follow-up and human studies of soy isoflavones on cognition. Expert Rev Neurother 7, 1549–64.

    Article  PubMed  CAS  Google Scholar 

  51. Bode, A.M., and Dong, Z. (2004) Beneficial effects of resveratrol. In: Bao Y., Fenwick R., eds. Phytochemicals in Health and Disease. New York: Marcel Dekker, Inc, 257–84.

    Chapter  Google Scholar 

  52. Gatz, S.A., and Wiesmuller, L. (2008) Take a break–resveratrol in action on DNA. Carcinogenesis 29, 321–32.

    Article  PubMed  CAS  Google Scholar 

  53. Harikumar, K.B., and Aggarwal, B.B. (2008) Resveratrol: A multitargeted agent for age-associated chronic diseases. Cell Cycle 7, 1020–35.

    Article  PubMed  CAS  Google Scholar 

  54. Kundu, J.K., and Surh, Y.J. (2008) Cancer chemopreventive and therapeutic potential of resveratrol: Mechanistic perspectives. Cancer Lett 269(2), 243–61.

    Article  PubMed  CAS  Google Scholar 

  55. Pirola, L., and Frojdo, S. (2008) Resveratrol: One molecule, many targets. IUBMB Life 60, 323–32.

    Article  PubMed  CAS  Google Scholar 

  56. Reagan-Shaw, S., Mukhtar, H., and Ahmad, N. (2008) Resveratrol imparts photoprotection of normal cells and enhances the efficacy of radiation therapy in cancer cells. Photochem Photobiol 84, 415–21.

    Article  PubMed  CAS  Google Scholar 

  57. Saiko, P., Szakmary, A., Jaeger, W., and Szekeres, T. (2008) Resveratrol and its analogs: Defense against cancer, coronary disease and neurodegenerative maladies or just a fad? Mutat Res 658, 68–94.

    Article  PubMed  CAS  Google Scholar 

  58. Boots, A.W., Haenen, G.R., and Bast, A. (2008) Health effects of quercetin: From antioxidant to nutraceutical. Eur J Pharmacol 585, 325–37.

    Article  PubMed  CAS  Google Scholar 

  59. Aggarwal, B.B., and Shishodia, S. (2006) Molecular targets of dietary agents for prevention and therapy of cancer. Biochem Pharmacol 71, 1397–421.

    Article  PubMed  CAS  Google Scholar 

  60. Ichimatsu, D., Nomura, M., Nakamura, S., Moritani, S., Yokogawa, K., Kobayashi, S., Nishioka, T., and Miyamoto, K. (2007) Structure-activity relationship of flavonoids for inhibition of epidermal growth factor-induced transformation of JB6 Cl 41 cells. Mol Carcinog 46, 436–45.

    Article  PubMed  CAS  Google Scholar 

  61. Bode, A.M., and Dong, Z. (2003) Signal transduction pathways: Targets for green and black tea polyphenols. J Biochem Mol Biol 36, 66–77.

    Article  CAS  Google Scholar 

  62. Graham, H.N. (1992) Green tea composition, consumption, and polyphenol chemistry. Prev Med 21, 334–50.

    Article  PubMed  CAS  Google Scholar 

  63. Yang, C.S., and Wang, Z.Y. (1993) Tea and cancer. J Natl Cancer Inst 85, 1038–49.

    Article  PubMed  CAS  Google Scholar 

  64. Chen, N.Y., Ma, W.Y., Yang, C.S., and Dong, Z. (2000) Inhibition of arsenite-induced apoptosis and AP-1 activity by epigallocatechin-3-gallate and theaflavins. J Environ Pathol Toxicol Oncol 19, 287–95.

    PubMed  CAS  Google Scholar 

  65. Dong, Z., Ma, W., Huang, C., and Yang, C.S. (1997) Inhibition of tumor promoter-induced activator protein 1 activation and cell transformation by tea polyphenols, (-)-epigallocatechin gallate, and theaflavins. Cancer Res 57, 4414–19.

    PubMed  CAS  Google Scholar 

  66. Ahn, H.Y., Hadizadeh, K.R., Seul, C., Yun, Y.P., Vetter, H., and Sachinidis, A. (1999) Epigallocathechin-3 gallate selectively inhibits the PDGF-BB-induced intracellular signaling transduction pathway in vascular smooth muscle cells and inhibits transformation of sis-transfected NIH 3T3 fibroblasts and human glioblastoma cells (A172). Mol Biol Cell 10, 1093–104.

    PubMed  CAS  Google Scholar 

  67. Barthelman, M., Bair, W.B., III, Stickland, K.K., Chen, W., Timmermann, B.N., Valcic, S., Dong, Z., and Bowden, G.T. (1998) (-)-Epigallocatechin-3-gallate inhibition of ultraviolet B-induced AP-1 activity. Carcinogenesis 19, 2201–04.

    Article  PubMed  CAS  Google Scholar 

  68. Nomura, M., Ma, W.Y., Huang, C., Yang, C.S., Bowden, G.T., Miyamoto, K., and Dong, Z. (2000) Inhibition of ultraviolet B-induced AP-1 activation by theaflavins from black Tea. Mol Carcinog 28, 148–55.

    Article  PubMed  CAS  Google Scholar 

  69. Chen, W., Dong, Z., Valcic, S., Timmermann, B.N., and Bowden, G.T. (1999) Inhibition of ultraviolet B–induced c-fos gene expression and p38 mitogen-activated protein kinase activation by (-)-epigallocatechin gallate in a human keratinocyte cell line. Mol Carcinog 24, 79–84.

    Article  PubMed  CAS  Google Scholar 

  70. Calautti, E., Missero, C., Stein, P.L., Ezzell, R.M., and Dotto, G.P. (1995) Fyn tyrosine kinase is involved in keratinocyte differentiation control. Genes Dev 9, 2279–91.

    Article  PubMed  CAS  Google Scholar 

  71. Matsumoto, T., Jiang, J., Kiguchi, K., Ruffino, L., Carbajal, S., Beltran, L., Bol, D.K., Rosenberg, M.P., and DiGiovanni, J. (2003) Targeted expression of c-Src in epidermal basal cells leads to enhanced skin tumor promotion, malignant progression, and metastasis. Cancer Res 63, 4819–28.

    PubMed  CAS  Google Scholar 

  72. Matsumoto, T., Jiang, J., Kiguchi, K., Carbajal, S., Rho, O., Gimenez-Conti, I., Beltran, L., and DiGiovanni, J. (2002) Overexpression of a constitutively active form of c-src in skin epidermis increases sensitivity to tumor promotion by 12-O-tetradecanoylphorbol-13-acetate. Mol Carcinog 33, 146–55.

    Article  PubMed  CAS  Google Scholar 

  73. Resh, M.D. (1998) Fyn, a Src family tyrosine kinase. The Int J Biochem Cell Biol 30, 1159–62.

    Article  CAS  Google Scholar 

  74. Li, X., Yang, Y., Hu, Y., Dang, D., Regezi, J., Schmidt, B.L., Atakilit, A., Chen, B., Ellis, D., and Ramos, D.M. (2003) Alphavbeta6-Fyn signaling promotes oral cancer progression. J Biol Chem 278, 41646–53.

    Article  PubMed  CAS  Google Scholar 

  75. Calautti, E., Grossi, M., Mammucari, C., Aoyama, Y., Pirro, M., Ono, Y., Li, J., and Dotto, G.P. (2002) Fyn tyrosine kinase is a downstream mediator of Rho/PRK2 function in keratinocyte cell-cell adhesion. J Cell Biol 156, 137–48.

    Article  PubMed  CAS  Google Scholar 

  76. He, Z., Tang, F., Ermakova, S., Li, M., Zhao, Q., Cho, Y.Y., Ma, W.Y., Choi, H.S., Bode, A.M., Yang, C.S., and Dong, Z. (2008) Fyn is a novel target of (-)-epigallocatechin gallate in the inhibition of JB6 Cl41 cell transformation. Mol Carcinog 47, 172–83.

    Article  PubMed  CAS  Google Scholar 

  77. Shim, J.H., Choi, H.S., Pugliese, A., Lee, S.Y., Chae, J.I., Choi, B.Y., Bode, A.M., and Dong, Z. (2008) (-)-Epigallocatechin gallate regulates CD3-mediated T-cell receptor signaling in leukemia through the inhibition of ZAP-70 kinase. J Biol Chem 283(42), 28370–79.

    Article  PubMed  CAS  Google Scholar 

  78. Chung, J.Y., Huang, C., Meng, X., Dong, Z., and Yang, C.S. (1999) Inhibition of activator protein 1 activity and cell growth by purified green tea and black tea polyphenols in H-ras-transformed cells: Structure-activity relationship and mechanisms involved. Cancer Res 59, 4610–17.

    PubMed  CAS  Google Scholar 

  79. Peng, G., Wargovich, M.J., and Dixon, D.A. (2006) Anti-proliferative effects of green tea polyphenol EGCG on Ha-Ras-induced transformation of intestinal epithelial cells. Cancer Lett 238, 260–70.

    Article  PubMed  CAS  Google Scholar 

  80. Shimizu, M., Deguchi, A., Lim, J.T., Moriwaki, H., Kopelovich, L., and Weinstein, I.B. (2005) (-)-Epigallocatechin gallate and polyphenon E inhibit growth and activation of the epidermal growth factor receptor and human epidermal growth factor receptor-2 signaling pathways in human colon cancer cells. Clin Cancer Res 11, 2735–46.

    Article  PubMed  CAS  Google Scholar 

  81. Yang, C.S., Chung, J.Y., Yang, G., Chhabra, S.K., and Lee, M.J. (2000) Tea and tea polyphenols in cancer prevention. J Nutr 130, 472S–8S.

    PubMed  CAS  Google Scholar 

  82. Chung, J.Y., Park, J.O., Phyu, H., Dong, Z., and Yang, C.S. (2001) Mechanisms of inhibition of the Ras-MAP kinase signaling pathway in 30.7b Ras 12 cells by tea polyphenols (-)-epigallocatechin-3-gallate and theaflavin-3,3′-digallate. FASEB J 15, 2022–24.

    PubMed  CAS  Google Scholar 

  83. Zykova, T.A., Zhang, Y., Zhu, F., Bode, A.M., and Dong, Z. (2005) The signal transduction networks required for phosphorylation of STAT1 at Ser727 in mouse epidermal JB6 cells in the UVB response and inhibitory mechanisms of tea polyphenols. Carcinogenesis 26, 331–42.

    Article  PubMed  CAS  Google Scholar 

  84. Mizuno, H., Cho, Y.Y., Zhu, F., Ma, W.Y., Bode, A.M., Yang, C.S., Ho, C.T., and Dong, Z. (2006) Theaflavin-3, 3′-digallate induces epidermal growth factor receptor downregulation. Mol Carcinog 45, 204–12.

    Article  PubMed  CAS  Google Scholar 

  85. He, Z., Ma, W.Y., Hashimoto, T., Bode, A.M., Yang, C.S., and Dong, Z. (2003) Induction of apoptosis by caffeine is mediated by the p53, Bax, and caspase 3 pathways. Cancer Res 63, 4396–401.

    PubMed  CAS  Google Scholar 

  86. Ito, K., Nakazato, T., Miyakawa, Y., Yamato, K., Ikeda, Y., and Kizaki, M. (2003) Caffeine induces G2/M arrest and apoptosis via a novel p53-dependent pathway in NB4 promyelocytic leukemia cells. J Cell Physiol 196, 276–83.

    Article  PubMed  CAS  Google Scholar 

  87. Lelo, A., Miners, J.O., Robson, R., and Birkett, D.J. (1986) Assessment of caffeine exposure: Caffeine content of beverages, caffeine intake, and plasma concentrations of methylxanthines. Clin Pharmacol Ther 39, 54–59.

    Article  PubMed  CAS  Google Scholar 

  88. Huang, M.T., Xie, J.G., Wang, Z.Y., Ho, C.T., Lou, Y.R., Wang, C.X., Hard, G.C., and Conney, A.H. (1997) Effects of tea, decaffeinated tea, and caffeine on UVB light-induced complete carcinogenesis in SKH-1 mice: Demonstration of caffeine as a biologically important constituent of tea. Cancer Res 57, 2623–29.

    PubMed  CAS  Google Scholar 

  89. Lu, G., Liao, J., Yang, G., Reuhl, K.R., Hao, X., and Yang, C.S. (2006) Inhibition of adenoma progression to adenocarcinoma in a 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced lung tumorigenesis model in A/J mice by tea polyphenols and caffeine. Cancer Res 66, 11494–501.

    Article  PubMed  CAS  Google Scholar 

  90. Nishikawa, A., Furukawa, F., Imazawa, T., Ikezaki, S., Hasegawa, T., and Takahashi, M. (1995) Effects of caffeine on glandular stomach carcinogenesis induced in rats by N-methyl-N’-nitro-N-nitrosoguanidine and sodium chloride. Food Chem Toxicol 33, 21–26.

    Article  PubMed  CAS  Google Scholar 

  91. Hosaka, S., Nagayama, H., and Hirono, I. (1984) Suppressive effect of caffeine on the development of hepatic tumors induced by 2-acetylaminofluorene in ACI rats. Gann 75, 1058–61.

    PubMed  CAS  Google Scholar 

  92. Lou, Y.R., Lu, Y.P., Xie, J.G., Huang, M.T., and Conney, A.H. (1999) Effects of oral administration of tea, decaffeinated tea, and caffeine on the formation and growth of tumors in high-risk SKH-1 mice previously treated with ultraviolet B light. Nutr Canc 33, 146–53.

    Article  CAS  Google Scholar 

  93. Jang, M.H., Shin, M.C., Kang, I.S., Baik, H.H., Cho, Y.H., Chu, J.P., Kim, E.H., and Kim, C.J. (2002) Caffeine induces apoptosis in human neuroblastoma cell line SK-N-MC. J Korean Med Sci 17, 674–78.

    PubMed  CAS  Google Scholar 

  94. Qi, W., Qiao, D., and Martinez, J.D. (2002) Caffeine induces TP53-independent G(1)-phase arrest and apoptosis in human lung tumor cells in a dose-dependent manner. Radiat Res 157, 166–74.

    Article  PubMed  CAS  Google Scholar 

  95. Hashimoto, T., He, Z., Ma, W.Y., Schmid, P.C., Bode, A.M., Yang, C.S., and Dong, Z. (2004) Caffeine Inhibits Cell Proliferation by G(0)/G(1) Phase Arrest in JB6 Cells. Cancer Res 64, 3344–49.

    Article  PubMed  CAS  Google Scholar 

  96. Nomura, M., Ichimatsu, D., Moritani, S., Koyama, I., Dong, Z., Yokogawa, K., and Miyamoto, K. (2005) Inhibition of epidermal growth factor-induced cell transformation and Akt activation by caffeine. Mol Carcinog 44, 67–76.

    Article  PubMed  CAS  Google Scholar 

  97. Hirsh, L., Dantes, A., Suh, B.S., Yoshida, Y., Hosokawa, K., Tajima, K., Kotsuji, F., Merimsky, O., and Amsterdam, A. (2004) Phosphodiesterase inhibitors as anti-cancer drugs. Biochem Pharmacol 68, 981–88.

    Article  PubMed  CAS  Google Scholar 

  98. Sadzuka, Y., Egawa, Y., Sugiyama, T., Sawanishi, H., Miyamoto, K., and Sonobe, T. (2000) Effects of 1-methyl-3-propyl-7-butylxanthine (MPBX) on idarubicin-induced antitumor activity and bone marrow suppression. Jpn J Cancer Res 91, 651–57.

    Article  PubMed  CAS  Google Scholar 

  99. Sadzuka, Y., Iwazaki, A., Sugiyama, T., Sawanishi, T., and Miyamoto, K. (1998) 1-Methyl-3-propyl-7-butylxanthine, a novel biochemical modulator, enhances therapeutic efficacy of adriamycin. Jpn J Cancer Res 89, 228–33.

    Article  PubMed  CAS  Google Scholar 

  100. Yoshida, Y., Hosokawa, K., Dantes, A., Tajima, K., Kotsuji, F., and Amsterdam, A. (2000) Theophylline and cisplatin synergize in down regulation of BCL-2 induction of apoptosis in human granulosa cells transformed by a mutated p53 (p53 val135) and Ha-ras oncogene. Int J Oncol 17, 227–35.

    PubMed  CAS  Google Scholar 

  101. Jiang, X., Lim, L.Y., Daly, J.W., Li, A.H., Jacobson, K.A., and Roberge, M. (2000) Structure-activity relationships for G2 checkpoint inhibition by caffeine analogs. Int J Oncol 16, 971–78.

    PubMed  CAS  Google Scholar 

  102. Rogozin, E.A., Lee, K.W., Kang, N.J., Yu, H., Nomura, M., Miyamoto, K., Conney, A.H., Bode, A.M., and Dong, Z. (2008) Inhibitory effects of caffeine analogues on neoplastic transformation: Structure-activity relationship. Carcinogenesis 29, 1228–34.

    Article  PubMed  CAS  Google Scholar 

  103. Surh, Y.J., Chun, K.S., Cha, H.H., Han, S.S., Keum, Y.S., Park, K.K., and Lee, S.S. (2001) Molecular mechanisms underlying chemopreventive activities of anti-inflammatory phytochemicals: Down-regulation of COX-2 and iNOS through suppression of NF-kappa B activation. Mutat Res 480–481, 243–68.

    PubMed  Google Scholar 

  104. Afzal, M., Al-Hadidi, D., Menon, M., Pesek, J., and Dhami, M.S. (2001) Ginger: An ethnomedical, chemical and pharmacological review. Drug Metabol Drug Interact 18, 159–90.

    Article  PubMed  CAS  Google Scholar 

  105. Grant, K.L., and Lutz, R.B. (2000) Ginger. Am J Health Syst Pharm 57, 945–47.

    PubMed  CAS  Google Scholar 

  106. Langner, E., Greifenberg, S., and Gruenwald, J. (1998) Ginger: History and use. Adv Ther 15, 25–44.

    PubMed  CAS  Google Scholar 

  107. Bode, A.M., Ma, W.Y., Surh, Y.J., and Dong, Z. (2001) Inhibition of epidermal growth factor-induced cell transformation and activator protein 1 activation by [6]-gingerol. Cancer Res 61, 850–53.

    PubMed  CAS  Google Scholar 

  108. Lee, E., Park, K.K., Lee, J.M., Chun, K.S., Kang, J.Y., Lee, S.S., and Surh, Y.J. (1998) Suppression of mouse skin tumor promotion and induction of apoptosis in HL-60 cells by Alpinia oxyphylla Miquel (Zingiberaceae). Carcinogenesis 19, 1377–81.

    Article  PubMed  CAS  Google Scholar 

  109. Lee, E., and Surh, Y.J. (1998) Induction of apoptosis in HL-60 cells by pungent vanilloids, [6]-gingerol and [6]-paradol. Cancer Lett 134, 163–68.

    Article  PubMed  CAS  Google Scholar 

  110. Surh, Y.J., Lee, E., and Lee, J.M. (1998) Chemoprotective properties of some pungent ingredients present in red pepper and ginger. Mutat Res 402, 259–67.

    Article  PubMed  CAS  Google Scholar 

  111. Surh, Y.J. (2002) Anti-tumor promoting potential of selected spice ingredients with antioxidative and anti-inflammatory activities: A short review. Food Chem Toxicol 40, 1091–97.

    Article  PubMed  CAS  Google Scholar 

  112. Keum, Y.S., Kim, J., Lee, K.H., Park, K.K., Surh, Y.J., Lee, J.M., Lee, S.S., Yoon, J.H., Joo, S.Y., Cha, I.H., and Yook, J.I. (2002) Induction of apoptosis and caspase-3 activation by chemopreventive [6]-paradol and structurally related compounds in KB cells. Cancer Lett 177, 41–47.

    Article  PubMed  CAS  Google Scholar 

  113. Dercks, W., and Creasy, L.L. (1989) The significance of stilbene phytoalexins in the Plasmopara viticola-grapevine interaction. Physiol Mol Plant Path 34, 189–202.

    Article  CAS  Google Scholar 

  114. Lee, K.W., Kang, N.J., Rogozin, E.A., Oh, S.M., Heo, Y.S., Pugliese, A., Bode, A.M., Lee, H.J., and Dong, Z. (2008) The resveratrol analogue 3,5,3′,4′,5′-pentahydroxy-trans-stilbene inhibits cell transformation via MEK. Int J Cancer 123, 2487–96.

    Article  PubMed  CAS  Google Scholar 

  115. Alessi, D.R., Cuenda, A., Cohen, P., Dudley, D.T., and Saltiel, A.R. (1995) PD 098059 is a specific inhibitor of the activation of mitogen-activated protein kinase kinase in vitro and in vivo. J Biol Chem 270, 27489–94.

    Article  PubMed  CAS  Google Scholar 

  116. Favata, M.F., Horiuchi, K.Y., Manos, E.J., Daulerio, A.J., Stradley, D.A., Feeser, W.S., Dyk, D.E.V., Pitts, W.J., Earl, R.A., Hobbs, F., Copeland, R.A., Magolda, R.L., Scherle, P.A., and Trzaskos, J.M. (1998) Identification of a novel inhibitor of mitogen-activated protein kinase kinase. J Biol Chem 273, 18623–32.

    Article  PubMed  CAS  Google Scholar 

  117. Ohren, J.F., Chen, H., Pavlovsky, A., Whitehead, C., Zhang, E., Kuffa, P., Yan, C., McConnell, P., Spessard, C., Banotai, C., Mueller, W.T., Delaney, A., Omer, C., Sebolt-Leopold, J., Dudley, D.T., Leung, I.K., Flamme, C., Warmus, J., Kaufman, M., Barrett, S., Tecle, H., and Hasemann, C.A. (2004) Structures of human MAP kinase kinase 1 (MEK1) and MEK2 describe novel noncompetitive kinase inhibition. Nat Struct Mol Biol 11, 1192–97.

    Article  PubMed  CAS  Google Scholar 

  118. Zykova, T.A., Zhu, F., Zhai, X., Ma, W.Y., Ermakova, S.P., Lee, K.W., Bode, A.M., and Dong, Z. (2008) Resveratrol directly targets COX-2 to inhibit carcinogenesis. Mol Carcinog 47(10), 797–805.

    Article  PubMed  CAS  Google Scholar 

  119. Watts, R.G., Huang, C., Young, M.R., Li, J.J., Dong, Z., Pennie, W.D., and Colburn, N.H. (1998) Expression of dominant negative Erk2 inhibits AP-1 transactivation and neoplastic transformation. Oncogene 17, 3493–98.

    Article  PubMed  CAS  Google Scholar 

  120. Anderson, N.G., Maller, J.L., Tonks, N.K., and Sturgill, T.W. (1990) Requirement for integration of signals from two distinct phosphorylation pathways for activation of MAP kinase. Nature 343, 651–53.

    Article  PubMed  CAS  Google Scholar 

  121. Sebolt-Leopold, J.S., Dudley, D.T., Herrera, R., Becelaere, K., Wiland, A., Gowan, R.C., Tecle, H., Barrett, S.D., Bridges, A., Przybranowski, S., Leopold, W.R., and Saltiel, A.R. (1999) Blockade of the MAP kinase pathway suppresses growth of colon tumors in vivo. Nat Med 5, 810–16.

    Article  PubMed  CAS  Google Scholar 

  122. Miean, K.H., and Mohamed, S. (2001) Flavonoid (myricetin, quercetin, kaempferol, luteolin, and apigenin) content of edible tropical plants. J Agr Food Chem 49, 3106–12.

    Article  CAS  Google Scholar 

  123. Cohen, M.S., Zhang, C., Shokat, K.M., and Taunton, J. (2005) Structural bioinformatics-based design of selective, irreversible kinase inhibitors. Science 308, 1318–21.

    Article  PubMed  CAS  Google Scholar 

  124. Smith, J.A., Poteet-Smith, C.E., Xu, Y., Errington, T.M., Hecht, S.M., and Lannigan, D.A. (2005) Identification of the first specific inhibitor of p90 ribosomal S6 kinase (RSK) reveals an unexpected role for RSK in cancer cell proliferation. Cancer Res 65, 1027–34.

    Article  PubMed  CAS  Google Scholar 

  125. Cho, Y.Y., Yao, K., Kim, H.G., Kang, B.S., Zheng, D., Bode, A.M., and Dong, Z. (2007) Ribosomal S6 kinase 2 is a key regulator in tumor promoter induced cell transformation. Cancer Res 67, 8104–12.

    Article  PubMed  CAS  Google Scholar 

  126. Shapiro, P. (2002) Ras-MAP kinase signaling pathways and control of cell proliferation: Relevance to cancer therapy. Crit Rev Clin Lab Sci 39, 285–330.

    Article  PubMed  CAS  Google Scholar 

  127. Gioeli, D., Mandell, J.W., Petroni, G.R., Frierson, H.F., Jr., and Weber, M.J. (1999) Activation of mitogen-activated protein kinase associated with prostate cancer progression. Cancer Res 59, 279–84.

    PubMed  CAS  Google Scholar 

  128. Oka, H., Chatani, Y., Hoshino, R., Ogawa, O., Kakehi, Y., Terachi, T., Okada, Y., Kawaichi, M., Kohno, M., and Yoshida, O. (1995) Constitutive activation of mitogen-activated protein (MAP) kinases in human renal cell carcinoma. Cancer Res 55, 4182–87.

    PubMed  CAS  Google Scholar 

  129. Waterhouse, A.L. (2002) Wine phenolics. Ann N Y Acad Sci 957, 21–36.

    Article  PubMed  CAS  Google Scholar 

  130. Soleas, G.J., Grass, L., Josephy, P.D., Goldberg, D.M., and Diamandis, E.P. (2006) A comparison of the anticarcinogenic properties of four red wine polyphenols. Clin Biochem 39, 492–97.

    Article  CAS  Google Scholar 

  131. Lee, K.W., Kang, N.J., Heo, Y.S., Rogozin, E.A., Pugliese, A., Hwang, M.K., Bowden, G.T., Bode, A.M., Lee, H.J., and Dong, Z. (2008) Raf and MEK protein kinases are direct molecular targets for the chemopreventive effect of quercetin, a major flavonol in red wine. Cancer Res 68, 946–55.

    Article  PubMed  CAS  Google Scholar 

  132. Kook, S.H., Son, Y.O., Jang, Y.S., Lee, K.Y., Lee, S.A., Kim, B.S., Lee, H.J., and Lee, J.C. (2008) Inhibition of c-Jun N-terminal kinase sensitizes tumor cells to flavonoid-induced apoptosis through down-regulation of JunD. Toxicol Appl Pharmacol 227, 468–76.

    Article  PubMed  CAS  Google Scholar 

  133. Kong, C.S., Kim, Y.A., Kim, M.M., Park, J.S., Kim, J.A., Kim, S.K., Lee, B.J., Nam, T.J., and Seo, Y. (2008) Flavonoid glycosides isolated from Salicornia herbacea inhibit matrix metalloproteinase in HT1080 cells. Toxicol In Vitro 22(7), 1742–48.

    Article  PubMed  CAS  Google Scholar 

  134. German, J.B., and Walzem, R.L. (2000) The health benefits of wine. Annu Rev Nutr 20, 561–93.

    Article  PubMed  CAS  Google Scholar 

  135. Hakkinen, S.H., Karenlampi, S.O., Heinonen, I.M., Mykkanen, H.M., and Torronen, A.R. (1999) Content of the flavonols quercetin, myricetin, and kaempferol in 25 edible berries. J Agr Food Chem 47, 2274–79.

    Article  CAS  Google Scholar 

  136. Ribeiro de Lima, M.T., Waffo-Teguo, P., Teissedre, P.L., Pujolas, A., Vercauteren, J., Cabanis, J.C., and Merillon, J.M. (1999) Determination of stilbenes (trans-astringin, cis- and trans-piceid, and cis- and trans-resveratrol) in Portuguese wines. J Agr Food Chem 47, 2666–70.

    Article  CAS  Google Scholar 

  137. Sellappan, S., and Akoh, C.C. (2002) Flavonoids and antioxidant capacity of Georgia-grown Vidalia onions. J Agr Food Chem 50, 5338–42.

    Article  CAS  Google Scholar 

  138. Aherne, S.A., and O’Brien, N.M. (1999) Protection by the flavonoids myricetin, quercetin, and rutin against hydrogen peroxide-induced DNA damage in Caco-2 and Hep G2 cells. Nutr Cancer 34, 160–66.

    Article  PubMed  CAS  Google Scholar 

  139. Echeverry, C., Blasina, F., Arredondo, F., Ferreira, M., Abin-Carriquiry, J.A., Vasquez, L., Aspillaga, A.A., Diez, M.S., Leighton, F., and Dajas, F. (2004) Cytoprotection by neutral fraction of tannat red wine against oxidative stress-induced cell death. J Agric Food Chem 52, 7395–99.

    Article  PubMed  CAS  Google Scholar 

  140. Chang, R.L., Huang, M.T., Wood, A.W., Wong, C.Q., Newmark, H.L., Yagi, H., Sayer, J.M., Jerina, D.M., and Conney, A.H. (1985) Effect of ellagic acid and hydroxylated flavonoids on the tumorigenicity of benzo[a]pyrene and (+/–)-7 beta, 8 alpha-dihydroxy-9 alpha, 10 alpha-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene on mouse skin and in the newborn mouse. Carcinogenesis 6, 1127–33.

    Article  PubMed  CAS  Google Scholar 

  141. Das, M., Khan, W.A., Asokan, P., Bickers, D.R., and Mukhtar, H. (1987) Inhibition of polycyclic aromatic hydrocarbon-DNA adduct formation in epidermis and lungs of SENCAR mice by naturally occurring plant phenols. Cancer Res 47, 767–73.

    PubMed  CAS  Google Scholar 

  142. Mukhtar, H., Das, M., Khan, W.A., Wang, Z.Y., Bik, D.P., and Bickers, D.R. (1988) Exceptional activity of tannic acid among naturally occurring plant phenols in protecting against 7,12-dimethylbenz(a)anthracene-, benzo(a)pyrene-, 3-methylcholanthrene-, and N-methyl-N-nitrosourea-induced skin tumorigenesis in mice. Cancer Res 48, 2361–65.

    PubMed  CAS  Google Scholar 

  143. Lu, J., Papp, L.V., Fang, J., Rodriguez-Nieto, S., Zhivotovsky, B., and Holmgren, A. (2006) Inhibition of Mammalian thioredoxin reductase by some flavonoids: Implications for myricetin and quercetin anticancer activity. Cancer Res 66, 4410–18.

    Article  PubMed  CAS  Google Scholar 

  144. Ko, C.H., Shen, S.C., Lee, T.J., and Chen, Y.C. (2005) Myricetin inhibits matrix metalloproteinase 2 protein expression and enzyme activity in colorectal carcinoma cells. Mol Cancer Ther 4, 281–90.

    PubMed  CAS  Google Scholar 

  145. Lee, K.W., Kang, N.J., Rogozin, E.A., Kim, H.G., Cho, Y.Y., Bode, A.M., Lee, H.J., Surh, Y.J., Bowden, G.T., and Dong, Z. (2007) Myricetin is a novel natural inhibitor of neoplastic cell transformation and MEK1. Carcinogenesis 28, 1918–27.

    Article  PubMed  CAS  Google Scholar 

  146. Jung, S.K., Lee, K.W., Byun, S., Kang, N.J., Lim, S.H., Heo, Y.S., Bode, A.M., Bowden, G.T., Lee, H.J., and Dong, Z. (2008) Myricetin suppresses UVB-induced skin cancer by targeting Fyn. Cancer Res 68, 6021–29.

    Article  PubMed  CAS  Google Scholar 

  147. Arora, A., Nair, M.G., and Strasburg, G.M. (1998) Antioxidant activities of isoflavones and their biological metabolites in a liposomal system. Arch Biochem Biophys 356, 133–41.

    Article  PubMed  CAS  Google Scholar 

  148. Sierens, J., Hartley, J.A., Campbell, M.J., Leathem, A.J., and Woodside, J.V. (2001) Effect of phytoestrogen and antioxidant supplementation on oxidative DNA damage assessed using the comet assay. Mutat Res 485, 169–76.

    Article  PubMed  CAS  Google Scholar 

  149. Widyarini, S. (2006) Protective effect of the isoflavone equol against DNA damage induced by ultraviolet radiation to hairless mouse skin. J Vet Sci (Suwon-si, Korea) 7, 217–23.

    Article  Google Scholar 

  150. Widyarini, S., Husband, A.J., and Reeve, V.E. (2005) Protective effect of the isoflavonoid equol against hairless mouse skin carcinogenesis induced by UV radiation alone or with a chemical cocarcinogen. Photochem Photobiol 81, 32–37.

    Article  PubMed  CAS  Google Scholar 

  151. Kang, N.J., Lee, K.W., Rogozin, E.A., Cho, Y.Y., Heo, Y.S., Bode, A.M., Lee, H.J., and Dong, Z. (2007) Equol, a metabolite of the soybean isoflavone daidzein, inhibits neoplastic cell transformation by targeting the MEK/ERK/p90RSK/activator protein-1 pathway. J Biol Chem 282, 32856–66.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work is supported by The Hormel Foundation, the Rochester Eagle’s Telethon, Hormel Foods, Pediatric Pharmaceuticals, University of Minnesota Office Vice President of Research, and grants from the American Institute for Cancer Research and NIH grants CA027502, CA081064, CA077646, CA088961, CA111356, CA074916, CA111536, CA120388, ES016548, and CA077451.

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  1. The Hormel Institute, University of Minnesota, Austin, MN, USA

    Ann M. Bode PHD & Zigang Dong MD, DR. PHD

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  1. Nutritional Science Research Group, Division of Cancer Prevention, National Institutes of Health, Executive Boulevard 6130, Rockville, 20892, Maryland, USA

    John A. Milner

  2. Nutritional and Cancer Biology, BIO5 Institute and Center for Toxicology, The University of Arizona, Tucson, 85721-0038, Arizona, USA

    Donato F. Romagnolo

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Bode, A.M., Dong, Z. (2010). Nutrient Signaling – Protein Kinase to Transcriptional Activation. In: Milner, J., Romagnolo, D. (eds) Bioactive Compounds and Cancer. Nutrition and Health. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-60761-627-6_6

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