Many population-based studies have highlighted the ability of macronutrients and micronutrients in vegetables and fruit to reduce the risk of cancer. Recently, attention has been focused on phytochemicals — non-nutritive components in the plant-based diet that possess cancer-preventive properties.
Despite remarkable progress in our understanding of the carcinogenic process, the mechanisms of action of most chemopreventive phytochemicals have not been fully elucidated.
Chemopreventive phytochemicals can block initiation or reverse the promotion stage of multistep carcinogenesis. They can also halt or retard the progression of precancerous cells into malignant ones.
Many molecular alterations associated with carcinogenesis occur in cell-signalling pathways that regulate cell proliferation and differentiation. One of the central components of the intracellular-signalling network that maintains homeostasis is the family of mitogen-activated protein kinases (MAPKs).
Numerous intracellular signal-transduction pathways converge with the activation of the transcription factors NF-κB and AP1. As these factors mediate pleiotropic effects of both external and internal stimuli in the cellular-signalling cascades, they are prime targets of diverse classes of chemopreventive phytochemicals.
Basic helix–loop–helix transcription factors such as NRF2 regulate expression of phase II enzymes, which detoxify carcinogens and protect against oxidative stress. A number of phytochemicals have been shown to induce expression of phase II enzymes via NRF2.
β-Catenin, a multifunctional protein that was originally identified as a component of cell–cell adhesion machinery, is another important molecular target for chemoprevention. Several dietary phytochemicals have been shown to target this molecule.
Chemoprevention refers to the use of agents to inhibit, reverse or retard tumorigenesis. Numerous phytochemicals derived from edible plants have been reported to interfere with a specific stage of the carcinogenic process. Many mechanisms have been shown to account for the anticarcinogenic actions of dietary constituents, but attention has recently been focused on intracellular-signalling cascades as common molecular targets for various chemopreventive phytochemicals.
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Doll, R. & Peto, R. The causes of cancer: quantitative estimates of avoidable risks of cancer in the United States today. J. Natl Cancer Inst. 66, 1191–1308 (1981).
Greenwald, P. Chemoprevention of cancer. Sci. Am. 275, 96–99 (1996).
Wattenberg, L. W. Chemoprevention of cancer. Cancer Res. 45, 1–8 (1985).
Manson, M. M. Cancer prevention: the potential for diet to modulate molecular signalling. Trends Mol. Med. 9, 11–18 (2003). This seminal review (together with reference 11) discusses the dietary modulation of several key signalling cascades from mechanistic viewpoints.
Milner, J. A., McDonald, S. S., Anderson, D. E. & Greenwald, P. Molecular targets for nutrients involved with cancer prevention. Nutr. Cancer 41, 1–16 (2001).
Gescher, A., Pastorino, U., Plummer, S. M. & Manson, M. M. Suppression of tumour development by substances derived from the diet: mechanisms and clinical implications. Br. J. Clin. Pharmacol. 45, 1–12 (1998).
Ashendel, C. L. Diet, signal transduction and carcinogenesis. J. Nutr. 125, 686S–691S (1995).
Kong, A. N. et al. Signal transduction events elicited by cancer prevention compounds. Mutat. Res. 480–481, 231–241 (2001).
Agarwal, R. Cell signaling and regulators of cell cycle as molecular targets for prostate cancer prevention by dietary agents. Biochem. Pharmacol. 60, 1051–1059 (2000).
Bode, A. M. & Dong, Z. Signal transduction pathways: targets for chemoprevention of skin cancer. Lancet Oncol. 1, 181–188 (2000).
Manson, M. M. et al. Blocking and suppressing mechanisms of chemoprevention by dietary constituents. Toxicol. Lett. 112–113, 499–505 (2000).
Owuor, E. D. & Kong, A. N. Antioxidants and oxidants regulated signal transduction pathways. Biochem. Pharmacol. 64, 765–770 (2002).
Beg, A. A. & Baltimore, D. An essential role for NF-κB in preventing TNF-α-induced cell death. Science 274, 782–784 (1996).
Wang, C. Y., Mayo, M. W., Korneluk, R. G., Goeddel, D. V. & Baldwin, A. S. Jr. NF-kB antiapoptosis: induction of TRAF1 and TRAF2 and c-IAP1 and c-IAP2 to suppress caspase-8 activation. Science 281, 1680–1683 (1998).
Visconti, R. et al. Expression of the neoplastic phenotype by human thyroid carcinoma cell lines requires NFκB p65 protein expression. Oncogene 15, 1987–1994 (1997).
Bharti, A. C. & Aggarwal, B. B. Nuclear factor-κ B and cancer: its role in prevention and therapy. Biochem. Pharmacol. 64, 883–888 (2002).
Bremner, P. & Heinrich, M. Natural products as targeted modulators of the nuclear factor-κB pathway. J. Pharm. Pharmacol. 54, 453–472 (2002).
Dong, Z., Birrer, M. J., Watts, R. G., Matrisian, L. M. & Colburn, N. H. Blocking of tumor promoter-induced AP-1 activity inhibits induced transformation in JB6 mouse epidermal cells. Proc. Natl Acad. Sci. USA 91, 609–613 (1994).
Dong, Z., Lavrovsky, V. & Colburn, N. H. Transformation reversion induced in JB6 RT101 cells by AP-1 inhibitors. Carcinogenesis 16, 749–756 (1995).
Dong, Z., Huang, C., Brown, R. E. & Ma, W. Y. Inhibition of activator protein 1 activity and neoplastic transformation by aspirin. J. Biol. Chem. 272, 9962–9970 (1997).
Huang, C., Ma, W. Y., Young, M. R., Colburn, N. & Dong, Z. Shortage of mitogen-activated protein kinase is responsible for resistance to AP-1 transactivation and transformation in mouse JB6 cells. Proc. Natl Acad. Sci. USA 95, 156–161 (1998).
Huang, C., Ma, W. Y. & Dong, Z. Requirement for phosphatidylinositol 3-kinase in epidermal growth factor-induced AP-1 transactivation and transformation in JB6 P+ cells. Mol. Cell. Biol. 16, 6427–6435 (1996).
Watts, R. G. et al. Expression of dominant negative Erk2 inhibits AP-1 transactivation and neoplastic transformation. Oncogene 17, 3493–3498 (1998). A crucial role of AP1 in malignant transformation, especially in the stage of tumour promotion, has been demonstrated in references 18–23. The signalling pathways that mediate AP1 activation have also been proposed in references 21–23.
Plummer, S. M. et al. Inhibition of cyclo-oxygenase 2 expression in colon cells by the chemopreventive agent curcumin involves inhibition of NF-κB activation via the NIK/IKK signalling complex. Oncogene 18, 6013–6020 (1999).
Surh, Y. J., Han, S. S., Keum, Y. S., Seo, H. J. & Lee, S. S. Inhibitory effects of curcumin and capsaicin on phorbol ester-induced activation of eukaryotic transcription factors, NF-κB and AP-1. Biofactors 12, 107–112 (2000).
Chun, K. S. et al. Curcumin inhibits phorbol ester-induced expression of cyclooxygenase-2 in mouse skin through suppression of extracellular signal-regulated kinase activity and NF–κB activation. Carcinogenesis 24, 1515–1524 (2003).
Singh, S. & Aggarwal, B. B. Activation of transcription factor NF-κ B is suppressed by curcumin (diferuloylmethane). J. Biol. Chem. 270, 24995–25000 (1995).
Bharti, A. C., Donato, N., Singh, S. & Aggarwal, B. B. Curcumin (diferuloylmethane) down-regulates the constitutive activation of nuclear factor-κ B and IκBα kinase in human multiple myeloma cells, leading to suppression of proliferation and induction of apoptosis. Blood 101, 1053–1062 (2003).
Philip, S. & Kundu, G. C. Osteopontin induces nuclear factor κB-mediated promatrix metalloproteinase-2 activation through IκBα/IKK signaling pathways, and curcumin (diferulolylmethane) down-regulates these pathways. J. Biol. Chem. 278, 14487–14497 (2003).
Park, K. K., Chun, K. S., Lee, J. M., Lee, S. S. & Surh, Y. J. Inhibitory effects of -gingerol, a major pungent principle of ginger, on phorbol ester-induced inflammation, epidermal ornithine decarboxylase activity and skin tumor promotion in ICR mice. Cancer Lett. 129, 139–144 (1998).
Bode, A. M., Ma, W. Y., Surh, Y. J. & Dong, Z. Inhibition of epidermal growth factor-induced cell transformation and activator protein 1 activation by -gingerol. Cancer Res. 61, 850–853 (2001).
Surh, Y. J. & Lee, S. S. Capsaicin, a double-edged sword: toxicity, metabolism, and chemopreventive potential. Life Sci. 56, 1845–1855 (1995).
Surh, Y. J. & Lee, S. S. Capsaicin in hot chili pepper: carcinogen, co-carcinogen or anticarcinogen? Food Chem. Toxicol. 34, 313–316 (1996).
Surh, Y. J. et al. Chemoprotective effects of capsaicin and diallyl sulfide against mutagenesis or tumorigenesis by vinyl carbamate and N-nitrosodimethylamine. Carcinogenesis 16, 2467–2471 (1995).
Surh, Y. J. More than spice: capsaicin in hot chili peppers makes tumor cells commit suicide. J. Natl Cancer Instit. 94, 1263–1265 (2002).
Park, K. K., Chun, K. S., Yook, J. I. & Surh, Y. J. Lack of tumor promoting activity of capsaicin, a principal pungent ingredient of red pepper, in mouse skin carcinogenesis. Anticancer Res. 18, 4201–4205 (1998).
Han, S. S. et al. Capsaicin suppresses phorbol ester-induced activation of NF-κB/Rel and AP-1 transcription factors in mouse epidermis. Cancer Lett. 164, 119–126 (2001).
Han, S. S., Keum, Y. S., Chun, K. S. & Surh, Y. J. Suppression of phorbol ester-induced NF-κB activation by capsaicin in cultured human promyelocytic leukemia cells. Arch. Pharm. Res. 25, 475–479 (2002).
Patel, P. S., Varney, M. L., Dave, B. J. & Singh, R. K. Regulation of constitutive and induced NF-κB activation in malignant melanoma cells by capsaicin modulates interleukin-8 production and cell proliferation. J. Interferon Cytokine Res. 22, 427–435 (2002).
Macho, A., Blazquez, M. V., Navas, P. & Munoz, E. Induction of apoptosis by vanilloid compounds does not require de novo gene transcription and activator protein 1 activity. Cell Growth Differ. 9, 277–286 (1998).
Kang, H. J. et al. Roles of JNK-1 and p38 in selective induction of apoptosis by capsaicin in ras-transformed human breast epithelial cells. Int. J. Cancer 103, 475–482 (2003).
Dong, Z., Ma, W., Huang, C. & Yang, C. S. Inhibition of tumor promoter-induced activator protein 1 activation and cell transformation by tea polyphenols, (−)-epigallocatechin gallate, and theaflavins. Cancer Res. 57, 4414–4419 (1997).
Nomura, M. et al. Inhibition of ultraviolet B-induced AP-1 activation by theaflavins from black tea. Mol. Carcinog. 28, 148–155 (2000).
Nomura, M., Ma, W., Chen, N., Bode, A. M. & Dong, Z. Inhibition of 12-O-tetradecanoylphorbol-13-acetate-induced NF-κB activation by tea polyphenols, (−)-epigallocatechin gallate and theaflavins. Carcinogenesis 21, 1885–1890 (2000).
Afaq, F., Adhami, V. M., Ahmad, N. & Mukhtar, H. Inhibition of ultraviolet B-mediated activation of nuclear factor κB in normal human epidermal keratinocytes by green tea Constituent (−)-epigallocatechin-3-gallate. Oncogene 22, 1035–1044 (2003).
Chung, J. Y., Huang, C., Meng, X., Dong, Z. & Yang, C. S. 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, 4610–4617 (1999). Provides the evidence for specific mechanisms of inhibition of the Mapk signalling pathway by tea polyphenols, including EGCG, as the molecular basis of their antineoplastic effects.
Yang, G. Y. et al. Effect of black and green tea polyphenols on c-jun phosphorylation and H2O2 production in transformed and non-transformed human bronchial cell lines: possible mechanisms of cell growth inhibition and apoptosis induction. Carcinogenesis 21, 2035–2039 (2000).
Nomura, M., Kaji, A., Ma, W., Miyamoto, K. & Dong, Z. Suppression of cell transformation and induction of apoptosis by caffeic acid phenethyl ester. Mol. Carcinog. 31, 83–89 (2001).
Pianetti, S., Guo, S., Kavanagh, K. T. & Sonenshein, G. E. Green tea polyphenol epigallocatechin-3 gallate inhibits Her-2/neu signaling, proliferation, and transformed phenotype of breast cancer cells. Cancer Res. 62, 652–655 (2002).
Masuda, M. et al. Epigallocatechin-3-gallate decreases VEGF production in head and neck and breast carcinoma cells by inhibiting EGFR-related pathways of signal transduction. J. Exp. Ther. Oncol. 2, 350–359 (2002).
Ahmad, N., Gupta, S. & Mukhtar, H. Green tea polyphenol epigallocatechin-3-gallate differentially modulates nuclear factor κB in cancer cells versus normal cells. Arch. Biochem. Biophys. 376, 338–346 (2000).
Lin, J. K., Liang, Y. C. & Lin-Shiau, S. Y. Cancer chemoprevention by tea polyphenols through mitotic signal transduction blockade. Biochem. Pharmacol. 58, 911–915 (1999).
Lin, J. K. Cancer chemoprevention by tea polyphenols through modulating signal transduction pathways. Arch. Pharm. Res. 25, 561–571 (2002).
Dampier, K. et al. Differences between human breast cell lines in susceptibility towards growth inhibition by genistein. Br. J. Cancer 85, 618–624 (2001).
Tacchini, L., Dansi, P., Matteucci, E. & Desiderio, M. A. Hepatocyte growth factor signal coupling to various transcription factors depends on triggering of Met receptor and protein kinase transducers in human hepatoma cells HepG2. Exp. Cell Res. 256, 272–281 (2000).
Wang, Y., Zhang, X., Lebwohl, M., DeLeo, V. & Wei, H. Inhibition of ultraviolet B (UVB)-induced c-fos and c-jun expression in vivo by a tyrosine kinase inhibitor genistein. Carcinogenesis 19, 649–654 (1998).
Davis, J. N., Kucuk, O. & Sarkar, F. H. Genistein inhibits NF-κB activation in prostate cancer cells. Nutr. Cancer 35, 167–174 (1999).
Li, Y. & Sarkar, F. H. Inhibition of nuclear factor κB activation in PC3 cells by genistein is mediated via Akt signaling pathway. Clin. Cancer Res. 8, 2369–2377 (2002).
Gong, L., Li, Y., Nedeljkovic-Kurepa, A. & Sarkar, F. H. Inactivation of NF-κB by genistein is mediated via Akt signaling pathway in breast cancer cells. Oncogene 22, 4702–4709 (2003). This study addresses a possible crosstalk between NF-κB and AKT signalling pathways, which are targets of antiproliferative activity exerted by genistein in human mammary carcinoma cells.
Chen, C. C., Sun, Y. T., Chen, J. J. & Chiu, K. T. TNF-α-induced cyclooxygenase-2 expression in human lung epithelial cells: involvement of the phospholipase C-γ 2, protein kinase C-α, tyrosine kinase, NF-κ B-inducing kinase, and I-κ B kinase 1/2 pathway. J. Immunol. 165, 2719–2728 (2000).
Nasuhara, Y., Adcock, I. M., Catley, M., Barnes, P. J. & Newton, R. Differential IκB kinase activation and IκBα degradation by interleukin-1β and tumor necrosis factor-α in human U937 monocytic cells. Evidence for additional regulatory steps in κB-dependent transcription. J. Biol. Chem. 274, 19965–19972 (1999).
Subbaramaiah, K. et al. Resveratrol inhibits cyclooxygenase-2 transcription and activity in phorbol ester-treated human mammary epithelial cells. J. Biol. Chem. 273, 21875–21882 (1998). This paper provides the first evidence for the inhibitory effects of resveratrol on the transcription and activity of COX2 by targeting CRE and PKC.
Subbaramaiah, K. et al. Resveratrol inhibits cyclooxygenase-2 transcription in human mammary epithelial cells. Ann. NY Acad. Sci. 889, 214–223 (1999).
Mouria, M. et al. Food-derived polyphenols inhibit pancreatic cancer growth through mitochondrial cytochrome C release and apoptosis. Int. J. Cancer 98, 761–769 (2002).
Banerjee, S., Bueso-Ramos, C. & Aggarwal, B. B. Suppression of 7,12-dimethylbenz(a)anthracene-induced mammary carcinogenesis in rats by resveratrol: role of nuclear factor-κB, cyclooxygenase 2, and matrix metalloprotease 9. Cancer Res. 62, 4945–4954 (2002).
Narayanan, B. A., Narayanan, N. K., Re, G. G. & Nixon, D. W. Differential expression of genes induced by resveratrol in LNCaP cells: p53-mediated molecular targets. Int. J. Cancer 104, 204–212 (2003).
She, Q. B., Bode, A. M., Ma, W. Y., Chen, N. Y. & Dong, Z. Resveratrol-induced activation of p53 and apoptosis is mediated by extracellular-signal-regulated protein kinases and p38 kinase. Cancer Res. 61, 1604–1610 (2001).
Yu, R. et al. Resveratrol inhibits phorbol ester and UV-induced activator protein 1 activation by interfering with mitogen-activated protein kinase pathways. Mol. Pharmacol. 60, 217–224 (2001).
Adhami, V. M., Afaq, F. & Ahmad, N. Suppression of ultraviolet B exposure-mediated activation of NF-κB in normal human keratinocytes by resveratrol. Neoplasia 5, 74–82 (2003).
Manna, S. K., Mukhopadhyay, A. & Aggarwal, B. B. Resveratrol suppresses TNF-induced activation of nuclear transcription factors NF-κ B, activator protein-1, and apoptosis: potential role of reactive oxygen intermediates and lipid peroxidation. J. Immunol. 164, 6509–6519 (2000).
Holmes-McNary, M. & Baldwin, A. S. Jr. Chemopreventive properties of trans-resveratrol are associated with inhibition of activation of the IκB kinase. Cancer Res. 60, 3477–3483 (2000).
Hayes, J. D. & McMahon, M. Molecular basis for the contribution of the antioxidant responsive element to cancer chemoprevention. Cancer Lett. 174, 103–113 (2001).
Itoh, K. et al. An Nrf2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements. Biochem. Biophys. Res. Commun. 236, 313–322 (1997). A pioneering study elucidating an essential role of NRF2 in the transcriptional induction of phase II enzymes. Targeted disruption of the Nrf2 gene abolished phase II enzyme induction (this paper) and Nrf2-deficient mice are prone to chemically-induced carcinogenesis (references 75 and 84).
Kwak, M. K. et al. Modulation of gene expression by cancer chemopreventive dithiolethiones through the Keap1-Nrf2 pathway. Identification of novel gene clusters for cell survival. J. Biol. Chem. 278, 8135–8145 (2003).
Ramos-Gomez, M. et al. Sensitivity to carcinogenesis is increased and chemoprotective efficacy of enzyme inducers is lost in nrf2 transcription factor-deficient mice. Proc. Natl Acad. Sci. USA 98, 3410–3415 (2001).
Chan, K., Han, X. D. & Kan, Y. W. An important function of Nrf2 in combating oxidative stress: detoxification of acetaminophen. Proc. Natl Acad. Sci. USA 98, 4611–4616 (2001).
McMahon, M. et al. The Cap'n'Collar basic leucine zipper transcription factor Nrf2 (NF-E2 p45-related factor 2) controls both constitutive and inducible expression of intestinal detoxification and glutathione biosynthetic enzymes. Cancer Res. 61, 3299–3307 (2001).
Cho, H. Y. et al. Role of NRF2 in protection against hyperoxic lung injury in mice. Am. J. Respir. Cell Mol. Biol. 26, 175–182 (2002).
Chanas, S. A. et al. Loss of the Nrf2 transcription factor causes a marked reduction in constitutive and inducible expression of the glutathione S-transferase Gsta1, Gsta2, Gstm1, Gstm2, Gstm3 and Gstm4 genes in the livers of male and female mice. Biochem. J. 365, 405–416 (2002).
Thimmulappa, R. K. et al. Identification of Nrf2-regulated genes induced by the chemopreventive agent sulforaphane by oligonucleotide microarray. Cancer Res. 62, 5196–5203 (2002).
Enomoto, A. et al. High sensitivity of Nrf2 knockout mice to acetaminophen hepatotoxicity associated with decreased expression of ARE-regulated drug metabolizing enzymes and antioxidant genes. Toxicol. Sci. 59, 169–177 (2001).
Ishii, T. et al. Transcription factor Nrf2 coordinately regulates a group of oxidative stress-inducible genes in macrophages. J. Biol. Chem. 275, 16023–16029 (2000).
Chan, K. & Kan, Y. W. Nrf2 is essential for protection against acute pulmonary injury in mice. Proc. Natl Acad. Sci. USA 96, 12731–12736 (1999).
Ramos-Gomez, M., Dolan, P. M., Itoh, K., Yamamoto, M. & Kensler, T. W. Interactive effects of nrf2 genotype and oltipraz on benzo[a]pyrene-DNA adducts and tumor yield in mice. Carcinogenesis 24, 461–467 (2003).
Kwak, M. K. et al. Role of phase 2 enzyme induction in chemoprotection by dithiolethiones. Mutat. Res. 480–481, 305–315 (2001).
Alam, J. et al. Nrf2, a Cap'n'Collar transcription factor, regulates induction of the heme oxygenase-1 gene. J. Biol. Chem. 274, 26071–26078 (1999).
Chan, J. Y. & Kwong, M. Impaired expression of glutathione synthetic enzyme genes in mice with targeted deletion of the Nrf2 basic-leucine zipper protein. Biochim. Biophys. Acta 1517, 19–26 (2000).
Nguyen, T., Huang, H. C. & Pickett, C. B. Transcriptional regulation of the antioxidant response element. Activation by Nrf2 and repression by MafK. J. Biol. Chem. 275, 15466–15473 (2000).
Itoh, K. et al. Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain. Genes Dev. 13, 76–86 (1999).
Dinkova-Kostova, A. T., Massiah, M. A., Bozak, R. E., Hicks, R. J. & Talalay, P. Potency of Michael reaction acceptors as inducers of enzymes that protect against carcinogenesis depends on their reactivity with sulfhydryl groups. Proc. Natl Acad. Sci. USA 98, 3404–3409 (2001).
Dinkova-Kostova, A. T. et al. Direct evidence that sulfhydryl groups of Keap1 are the sensors regulating induction of phase 2 enzymes that protect against carcinogens and oxidants. Proc. Nat. Acad. Sci. USA 99, 11908–11913 (2002). This work provides the first direct evidence for the formation of complexes of KEAP1 with the NEH2 domain of NRF2, which is disrupted by phase II enzyme inducers, such as sulphoraphane. Sulphoraphane directly reacts with critical cysteine residues of KEAP1 stoichiometrically.
Wolf, C. R. Chemoprevention: increased potential to bear fruit. Proc. Natl Acad. Sci. USA 98, 2941–2943 (2001).
Na, H. -K. & Surh, Y. -J. Peroxisome proliferator–activated receptor γ (PPARγ) ligands as bifunctional regulators of cell proliferation. Biochem. Pharmacol. 66, 1381–1391 (2003).
Yu, R. et al. Activation of mitogen-activated protein kinases by green tea polyphenols: potential signaling pathways in the regulation of antioxidant-responsive element-mediated phase II enzyme gene expression. Carcinogenesis 18, 451–456 (1997). Here, the molecular basis for induction of phase II enzymes by green-tea polyphenol was demonstrated. Green-tea polyphenol stimulates transcription of phase II enzymes through ARE, which seems to be regulated by MAPK.
Chen, C., Yu, R., Owuor, E. D. & Kong, A. N. Activation of antioxidant-response element (ARE), mitogen-activated protein kinases (MAPKs) and caspases by major green tea polyphenol components during cell survival and death. Arch. Pharm. Res. 23, 605–612 (2000).
Kong, A. N. et al. Induction of xenobiotic enzymes by the MAP kinase pathway and the antioxidant or electrophile response element (ARE/EpRE). Drug Metab. Rev. 33, 255–271 (2001).
Yu, R. et al. Role of a mitogen-activated protein kinase pathway in the induction of phase II detoxifying enzymes by chemicals. J. Biol. Chem. 274, 27545–27552 (1999).
Morimitsu, Y. et al. A sulforaphane analogue that potently activates the Nrf2-dependent detoxification pathway. J. Biol. Chem. 277, 3456–3463 (2002).
Balogun, E. et al. Curcumin activates the haem oxygenase-1 gene via regulation of Nrf2 and the antioxidant-responsive element. Biochem. J. 371, 887–895 (2003).
Dickinson, D. A., Iles, K. E., Zhang, H., Blank, V. & Forman, H. J. Curcumin alters EpRE and AP-1 binding complexes and elevates glutamate-cysteine ligase gene expression. FASEB J. 17, 473–475 (2003).
Kemler, R. From cadherins to catenins: cytoplasmic protein interactions and regulation of cell adhesion. Trends Genet. 9, 317–321 (1993).
Aberle, H., Schwartz, H. & Kemler, R. Cadherin-catenin complex: protein interactions and their implications for cadherin function. J. Cell Biochem. 61, 514–523 (1996).
Morin, P. J. β-catenin signaling and cancer. Bioessays 21, 1021–1030 (1999).
Munemitsu, S., Albert, I., Souza, B., Rubinfeld, B. & Polakis, P. Regulation of intracellular β-catenin levels by the adenomatous polyposis coli (APC) tumor-suppressor protein. Proc. Natl Acad. Sci. USA 92, 3046–3050 (1995).
Rubinfeld, B. et al. Binding of GSK3β to the APC-β-catenin complex and regulation of complex assembly. Science 272, 1023–1026 (1996). This important paper provides evidence for the role of GSK-3β as a regulator of APC β-catenin binding. APC is a good substrate for GSK.
Orford, K., Crockett, C., Jensen, J. P., Weissman, A. M. & Byers, S. W. Serine phosphorylation-regulated ubiquitination and degradation of β-catenin. J. Biol. Chem. 272, 24735–24738 (1997).
Sakanaka, C. Phosphorylation and regulation of β-catenin by casein kinase I epsilon. J. Biochem. 132, 697–703 (2002).
Amit, S. et al. Axin-mediated CKI phosphorylation of β-catenin at Ser 45: a molecular switch for the Wnt pathway. Genes Dev. 16, 1066–1076 (2002).
Liu, C. et al. Control of β-catenin phosphorylation/degradation by a dual-kinase mechanism. Cell 108, 837–847 (2002).
Grimes, C. A. & Jope, R. S. The multifaceted roles of glycogen synthase kinase 3β in cellular signaling. Prog. Neurobiol. 65, 391–426 (2001).
Polakis, P. Wnt signaling and cancer. Genes Dev. 14, 1837–1851 (2000).
Satoh, S. et al. AXIN1 mutations in hepatocellular carcinomas, and growth suppression in cancer cells by virus-mediated transfer of AXIN1. Nature Genet. 24, 245–250 (2000).
Novak, A. & Dedhar, S. Signaling through β-catenin and Lef/Tcf. Cell Mol. Life Sci. 56, 523–537 (1999).
Wong, N. A. & Pignatelli, M. β-catenin: a linchpin in colorectal carcinogenesis? Am. J. Pathol. 160, 389–401 (2002).
Kolligs, F. T. et al. ITF-2, a downstream target of the Wnt/TCF pathway, is activated in human cancers with β-catenin defects and promotes neoplastic transformation. Cancer Cell 1, 145–155 (2002).
Araki, Y. et al. Regulation of cyclooxygenase-2 expression by the Wnt and ras pathways. Cancer Res. 63, 728–734 (2003).
Mahmoud, N. N. et al. Plant phenolics decrease intestinal tumors in an animal model of familial adenomatous polyposis. Carcinogenesis 21, 921–927 (2000).
Jaiswal, A. S., Marlow, B. P., Gupta, N. & Narayan, S. β-catenin-mediated transactivation and cell–cell adhesion pathways are important in curcumin (diferuylmethane)-induced growth arrest and apoptosis in colon cancer cells. Oncogene 21, 8414–8427 (2002).
Joe, A. K. et al. Resveratrol induces growth inhibition, S-phase arrest, apoptosis, and changes in biomarker expression in several human cancer cell lines. Clin. Cancer Res. 8, 893–903 (2002).
Dashwood, W. M., Orner, G. A. & Dashwood, R. H. Inhibition of β-catenin/Tcf activity by white tea, green tea, and epigallocatechin-3-gallate (EGCG): minor contribution of H(2)O(2) at physiologically relevant EGCG concentrations. Biochem. Biophys. Res. Commun. 296, 584–588 (2002).
Orner, G. A. et al. Response of Apcmin and A33ΔNβ-cat mutant mice to treatment with tea, sulindac, and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). Mutat. Res. 506–507, 121–127 (2002).
Blum, C. A. et al. β-Catenin mutation in rat colon tumors initiated by 1,2-dimethylhydrazine and 2-amino-3-methylimidazo[4,5-f]quinoline, and the effect of post-initiation treatment with chlorophyllin and indole-3-carbinol. Carcinogenesis 22, 315–320 (2001).
Meng, Q. et al. Suppression of breast cancer invasion and migration by indole-3-carbinol: associated with up-regulation of BRCA1 and E-cadherin/catenin complexes. J. Mol. Med. 78, 155–165 (2000).
Brack, M. E. et al. The citrus methoxyflavone tangeretin affects human cell–cell interactions. Adv. Exp. Med. Biol. 505, 135–139 (2002).
McEntee, M. F., Chiu, C. H. & Whelan, J. Relationship of β-catenin and Bcl-2 expression to sulindac-induced regression of intestinal tumors in Min mice. Carcinogenesis 20, 635–640 (1999).
Dihlmann, S., Siermann, A. & von Knebel Doeberitz, M. The nonsteroidal anti-inflammatory drugs aspirin and indomethacin attenuate β-catenin/TCF-4 signaling. Oncogene 20, 645–653 (2001).
Mori, H. et al. Chemoprevention of large bowel carcinogenesis; the role of control of cell proliferation and significance of β-catenin-accumulated crypts as a new biomarker. Eur. J. Cancer Prev. 11 (Suppl. 2), S71–S75 (2002).
Surh, Y. Molecular mechanisms of chemopreventive effects of selected dietary and medicinal phenolic substances. Mut. Res. 428, 305–327 (1999).
Das, R., Mahabeleshwar, G. H. & Kundu, G. C. Osteopontin stimulates cell motility and nuclear factor κB-mediated secretion of urokinase type plasminogen activator through phosphatidylinositol 3–kinase/Akt signaling pathways in breast cancer cells. J. Biol. Chem. (in the press).
Yang, F. et al. The green tea polyphenol (-)-epigallocatechin-3-gallate blocks nuclear factor-κB activation by inhibiting Iκ B kinase activity in the intestinal epithelial cell line IEC-6. Mol. Pharm. 60, 528–533 (2001).
Huang, H. C., Nguyen, T. & Pickett, C. B. Phosphorylation of Nrf2 at Ser-40 by protein kinase C regulates antioxidant response element-mediated transcription. J. Biol. Chem. 277, 42769–42774 (2002).
Kang, K. W., Park, E. Y. & Kim, S. G. Activation of CCAAT/enhancer-binding protein β by 2'-amino-3'-methoxyflavone (PD98059) leads to the induction of glutathione S-transferase A2. Carcinogenesis 24, 475–482 (2003).
Lee, J. M., Hanson, J. M., Chu, W. A. & Johnson, J. A. Phosphatidylinositol 3-kinase, not extracellular signal-regulated kinase, regulates activation of the antioxidant-responsive element in IMR-32 human neuroblastoma cells. J. Biol. Chem. 276, 20011–20016 (2001).
The author thanks the members of his laboratory, especially H.K. Na, J.K. Kundu, K.S. Chun, J.S. Lee, M.H. Chung, E. Kim and J.M. Lee (currently at the University of Wisconsin-Madison) for having prepared the table and illustrations, as well as sorting out the references. Work in the author's laboratory is supported by research grants from the Korea Institute of Science and Technology Evaluation and Planning (KISTEP) for functional food research and development, Ministry of Science and Technology.
- LUCIFERASE-REPORTER-GENE ASSAY
A recombinant method that is used to measure transcriptional activity in which the regulatory sequence (for example, promoter or enhancer) of interest is joined to a firefly luciferase gene that, following activation, produces light from luciferin in the presence of ATP added to the assay mixture. The relative intensity of the light emission is measured with a luminometer.
(Cyclic AMP response element binding protein). CREB is a leucine zipper transcription factor that binds to DNA at the cyclic AMP response element (CRE) as a homo- or heterodimer. It has pivotal roles in the control of cellular proliferation and differentiation, apoptosis, intermediary metabolism, inflammation and numerous other responses, particularly in hepatocytes, adipocytes and haematopoietic cells.
- PHASE II ENZYMES
A group of xenobiotic metabolizing enzymes that are mainly involved in the inactivation and excretion of carcinogens and other toxic chemical substances.
- ANTIOXIDANT-RESPONSIVE ELEMENT
(ARE). A specific DNA-promoter-binding region that can be transcriptionally activated by numerous antioxidants and/or electrophiles. Many stress-response genes encoding phase II detoxification or antioxidant enzymes such as glutathione S-transferase, quinone reductase, and heme oxygenase-1 — which provide defence against cellular oxidative stress — have this element in their 5′-flanking region to facilitate the transcription process.
- REDOX CYCLING
A reciprocal transformation between an oxidant and its reductive counterpart. An example is conversion of catechol to quinone via semiquinone or vice versa.
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