Signalling Pathways as Targets in Cancer Prevention

  • M. M. Manson
  • L. M. Howells
  • E. A. Hudson
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 156)


Normal cells constantly receive signals from their external and internal environments which determine whether they proliferate, differentiate, arrest cell growth, or undergo apoptosis. Transformed cells either fail to respond or receive inappropriate signals which favor proliferation and avoidance of apoptosis. Thus, it is no coincidence that many oncogenes and tumor suppressor genes are components of signalling pathways. Despite the great variety of cancer cell genotypes, it has been suggested that transformation is a result of a few essential changes in cell physiology which collectively dictate malignant phenotype. These acquired characteristics are self-sufficiency in growth signals, insensitivity to growth inhibitory signals, evasion of apoptosis, limitless replicative potential, sustained angiogenesis, and tissue invasion and metastasis (Hanahan and Weinberg 2000). There are now examples, at least from in vitro studies, of chemopreventive agents which influence each of these acquired characteristics, suggesting the possibility of intervention at many stages of the carcinogenic process. As our understanding of the cell circuitry involved increases (Hanahan and Weinberg 2000), exciting new opportunities to target deregulated signalling pathways present themselves.


Chemopreventive Agent Aberrant Crypt Focus Mitogen Activate Protein Kinase Pathway Mitogen Activate Protein Kinase Cascade Epidermal Growth Factor Receptor Family 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Agarwal R (2000) Cell signalling and regulators of cell cycle as molecular targets for prostate cancer prevention by dietary agents. Biochem Pharmacol 6:1051–1059CrossRefGoogle Scholar
  2. Alessi DR (2001) Discovery of PDK1, one of the missing links in insulin signal transduction. Biochem Soc Trans 29:1–14PubMedCrossRefGoogle Scholar
  3. Barkett M, Gilmore TD (1999) Control of apoptosis by Rel/NF-κB transcription factors. Oncogene 18:6910–6924PubMedCrossRefGoogle Scholar
  4. Bergers G, Javaherian K, Lo K-M, Folkman J, Hanahan D (1999) Effects of angiogen-esis in multistage carcinogenesis in mice. Science 284:808–812PubMedCrossRefGoogle Scholar
  5. Bierhaus A, Zhang Y, Quehenberger P, Luther T, Haase M, Muller M, Mackman N, Ziegler R, Nawroth PP (1997) The dietary pigment curcumin reduces endothelial tissue factor gene by inhibiting binding of AP-1 to the DNA and activation of NF-κB. Thrombosis Haemostasis 77:772–782Google Scholar
  6. Biswas DK, Cruz AP, Gansberger E, Pardee AB (2000) Epidermal growth factor-induced nuclear factor κB activation: a major pathway of cell cycle progression in estrogen-receptor negative breast cancer cells. Proc Natl Acad Sci USA 97: 8542–8547PubMedCrossRefGoogle Scholar
  7. Biswas DK, Dai SC, Cruz A, Weiser B, Graner E, Pardee AB (2001) The nuclear factor kappa B (NF-κB): a potential therapeutic target for estrogen receptor negative breast cancers. Proc Natl Acad Sci USA 98:10386–10391PubMedCrossRefGoogle Scholar
  8. Bradlow HL, Michnovicz JJ, Halsper M, Miller DG, Wong GY, Osborne MP (1994) Long term responses of women to I3C or a high fibre diet. Cancer Epidemiol Biomarkers Prev 3:591–595PubMedGoogle Scholar
  9. Bundred NJ, Chan K, Anderson NG (2001) Studies of epidermal growth factor inhibition in breast cancer. Endocr Relat Cancer 8:183–189PubMedCrossRefGoogle Scholar
  10. Cantrell D (2001) Phosphoinositide 3-kinase signalling pathways. J Cell Sci 114: 1439–1445PubMedGoogle Scholar
  11. Chan MM-Y, Huang HI, Fenton MR, Fong D (1998) In vivo inhibition of nitric oxide synthase gene expression by curcumin, a cancer preventive natural product with antiinflammatory properties. Biochem Pharmacol 55:1955–1962PubMedCrossRefGoogle Scholar
  12. Chen Y-R, Tan T-H (1998) Inhibition of c-jun N-terminal kinase (JNK) signalling pathway by curcumin. Oncogene 17:173–178PubMedCrossRefGoogle Scholar
  13. Cheng JQ, Godwin AK, Bellacosa A, Taguchi T, Franke TF, Hamilton YC, Tsichlis PN Testa JR (1992) Akt2, a putative oncogene encoding a member of a sub family of protein-serine/threonine kinases, is amplified in ovarian cancer. Proc Natl Acad Sci USA 89:9267–9271PubMedCrossRefGoogle Scholar
  14. Cheng JQ, Ruggeri B, Klein WM, Sonoda G, Altomare DA, Watson DK, Testa JR (1996) Amplification of Akt2 in human pancreatic cells and inhibition of Akt2 expression and tumorigenicity by antisense RNA. Proc Natl Acad Sci USA 93:3636–3641PubMedCrossRefGoogle Scholar
  15. Cheng M, Sexl V, Sherr CJ, Roussel MF (1998) Assembly of cyclin D-dependent kinase and titration of p27kip1 regulated by mitogen-activated protein kinase kinase (MEK1) Proc Natl Acad Sci USA 95:1091–1096PubMedCrossRefGoogle Scholar
  16. Cover CM, Hsieh SJ, Tran SH, Hallden G, Kim GS, Bjeldanes LF, Firestone GL (1998) Indole-3-carbinol inhibits the expression of cyclin-dependent kinase-6 and induces a G1 cell cycle arrest of human breast cancer cells independent of estrogen receptor signalling. J Biol Chem 273:3838–3847PubMedCrossRefGoogle Scholar
  17. Cram EJ, Liu BD, Bjeldanes LF and Firestone GL (2001) Indole-3-carbinol inhibits CDK6 expression in human MCF-7 breast cancer cells by disrupting Sp1 transcription factor interactions with a composite element in the CDK6 gene promoter. J Biol Chem 276:22332–22340PubMedCrossRefGoogle Scholar
  18. Chung FL, Conaway CC, Rao CV, Reddy BS (2000) Chemoprevention of colonic aberrant crypt foci in Fischer rats by sulforaphane and phenethyl isothiocyanate. Carcinogenesis 21:2287–2291PubMedCrossRefGoogle Scholar
  19. Davis RJ (2000) Signal transduction by the JNK group of MAP kinases. Cell 103: 239–252PubMedCrossRefGoogle Scholar
  20. De Flora S, Izzotti A, D’Agostini F, Balansky RM (2001) Mechanisms of N-acetylcysteine in the prevention of DNA damage and cancer, with special reference to smoking related end-points. Carcinogenesis 22:999–1013PubMedCrossRefGoogle Scholar
  21. Derynck R, Akhurst R, Balmain A (2001) TGFβ signalling in tumor suppression and cancer progression. Nature Genetics 29:117–129PubMedCrossRefGoogle Scholar
  22. Dormond O, Foletti A, Paroz C, Ruegg C, (2001) NSAIDs inhibit αVb3 integrin-mediated and Cdc42/Rac-dependent endothelial-cell spreading, migration and angiogenesis. Nature Med 7:1041–1047PubMedCrossRefGoogle Scholar
  23. Downward J (1999) How Bad phosphorylation is good for survival. Nature Cell Biol LE33-E35Google Scholar
  24. Fambrough D, McClure K, Kaslauskas A, Lander E (1999) Diverse signalling pathways activated by growth factor receptors induce broadly overlapping, rather than independent sets of genes. Cell 97:727–741PubMedCrossRefGoogle Scholar
  25. Fischer PM, Lane DP (2000) Inhibitors of cyclin-dependent kinases as anticancer therapeutics. Curr Med Chem 7:1213–1245PubMedCrossRefGoogle Scholar
  26. Gerhauser C, You M, Lui J, Moriaty RM, Hawthorne M, Mehta RG, Moon RC, Pezzuto JM (1997) Cancer chemopreventive potential of sulforamate, a novel analogue of sulforaphane that induces phase 2 drug-metabolizing enzymes. Cancer Res 57: 272–278PubMedGoogle Scholar
  27. Gille H, Downward J (1999) Multiple ras effector pathways contribute to G1 cell cycle progression. J Biol Chem 274:22033–22040PubMedCrossRefGoogle Scholar
  28. Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100:57–70PubMedCrossRefGoogle Scholar
  29. Heiss E, Herhaus C, Klimo K, Bartsch H, Gerhauser C (2001) Nuclear factor kB is a molecular target for sulforaphane-mediated antiinflammatory mechanisms. J Biol Chem 276:32008–32015PubMedCrossRefGoogle Scholar
  30. Hietanen S, Lain S, Krausz E, Blattner C, Lane DP (2000) Activation of p53 in cervical carcinoma cells by small molecules. Proc Natl Acad Sci USA 97:8501–8506PubMedCrossRefGoogle Scholar
  31. Hong R-L, Spohn WH, Hung M-C (1999) Curcumin inhibits tyrosine kinase activity of pl85neu and also depletes pl85neu1. Clin Cancer Res 5:1884–1891PubMedGoogle Scholar
  32. Howells L, Gallacher-Horley B, Hudson EA, Manson MM (2001) Indole-3-carbinol inhibits PKB/Akt phosphorylation in a human breast tumor cell line. Proc Am Assoc Cancer Res 42:312Google Scholar
  33. Hsu A-L, Ching T-T, Wang D-S, Song X, Rangnekar VM, Chen C-S (2000) The cyclooxygenase-2 inhibitor celecoxib induces apoptosis by blocking Akt activation in human prostate cancer cells independently of Bcl-2. J Biol Chem 275: 11397–11403PubMedCrossRefGoogle Scholar
  34. Huang T-S, Lee S-C, Lin J-K (1991) Suppression of c-Jun/AP-1 activation by an inhibitor of tumor promotion in mouse fibroblast cells. Proc Natl Acad Sci 88: 5292–5296PubMedCrossRefGoogle Scholar
  35. Hupp TR, Lane DP, Ball KL (2000) Strategies for manipulating the p53 pathway in the treatment of human cancer. Biochem J 352:1–17PubMedCrossRefGoogle Scholar
  36. Ichijo H (1999) From receptors to stress-activated MAP kinases. Oncogene 18: 6087–6093PubMedCrossRefGoogle Scholar
  37. Israel A (2000) The IKK complex: an integrator of all signals that activate NF-kB? Trends Cell Biol 10:129–133PubMedCrossRefGoogle Scholar
  38. Jobin C, Bradham CA, Russo MP, Juma B, Narula AS, Brenner DA, Sartor RB (1999) Curcumin blocks cytokine-mediated NF-kB activation and proinflammatory gene expression by inhibiting inhibitory factor I-kB kinase activity. J Immunol 163:3474–3483PubMedGoogle Scholar
  39. Jordan VC (2001) Selective estrogen receptor modulation: a personal perspective. Cancer Res 61:5683–5687PubMedGoogle Scholar
  40. Kirschbaum MH, Yarden Y (2000) The ErbB/HER family of receptor tyrosine kinases: a potential target for chemoprevention of epithelial neoplasms. J Cell Biochem 34:52–60CrossRefGoogle Scholar
  41. Komarova EA, Gudkov AV (2001) Chemoprotection from p53-dependent apoptosis: potential clinical applications of p53 inhibitors. Biochem Pharmacol 62:657–667PubMedCrossRefGoogle Scholar
  42. Kong AN, Mandlekar S, Yu R, Lei W, Fasanmande A (1999) Pharmacodynamics and toxicodynamics of drug action: signalling in cell survival and cell death. Pharm Res 16:790–798PubMedCrossRefGoogle Scholar
  43. Korutla L, Cheung JY, Mendelsohn J, Kumar R (1995) Inhibition of ligand-induced activation of epidermal growth factor receptor tyrosine phosphorylation by curcumin. Carcinogenesis 16:1741–1745PubMedCrossRefGoogle Scholar
  44. Kumar A, Dhawan S, Hardegen NJ, Aggarwal BB (1998) Curcumin (diferuloyl-methane) inhibition of tumor necrosis factor (TNF)-mediated adhesion of monocytes to endothelial cells by suppression of cell surface expression of adhesion molecules and of nuclear factor- κB activation. Biochem Pharmacol 55:775–783PubMedCrossRefGoogle Scholar
  45. Liang Y-C, Lin-Shiau S-Y, Chen C-F, Lin J-K (1999) Inhibition of cyclin-dependent kinases 2 and 4 activities as well as induction of Cdk inhibitors p21 and p27 during growth arrest of human breast carcinoma cells by (-)-epigallocatechin-3-gallate. J Cell Biochem 75:1–12PubMedCrossRefGoogle Scholar
  46. Lawlor MA, Alessi, DR (2001) PKB/Akt: a key mediator of cell proliferation, survival and insulin response? J Cell Science 114:2903–2910PubMedGoogle Scholar
  47. Lavoie JN, L’Allemain G, Brunet A, Mueller R, Pouyssegur J (1996) Cyclin D1 expression is regulated positively by the p42/p44 MAPK and negatively by the p38/HOGMAPKpathway. J Biol Chem 271:20608–20616PubMedCrossRefGoogle Scholar
  48. Levitt ML, Koty PP (1999) Tyrosine kinase inhibitors in preclinical development. Invest New Drugs 17:213–226PubMedCrossRefGoogle Scholar
  49. Liu K-H, Yao S, Kirschenbaum A, Levine AC (1998) NS398, a selective cyclooxygenase-2 inhibitor, induces apoptosis and down regulates Bcl-2 expression in LNCaP cells. Cancer Res 58; 4245–4249PubMedGoogle Scholar
  50. McCormick F (2000) Signalling networks that cause cancer. Trends Cell Biol 9:M53-M56CrossRefGoogle Scholar
  51. Malumbres M, Barbacid M (2001) To cycle or not to cycle: a critical decision in cancer. Nature Rev Cancer 1:222–231CrossRefGoogle Scholar
  52. Manson MM, Holloway KA, Howells LM, Hudson EA, Plummer SM, Squires MS, Prigent SA (2000) Modulation of signal-transduction pathways by chemopreven-tive agents. Biochem Soc Trans 28:7–12PubMedGoogle Scholar
  53. Manson MM, Gescher A, Hudson EA, Plummer SM, Squires MS, Prigent SA (2000) Blocking and suppressing mechanisms of chemoprevention by dietary constituents. Toxicol Letters 112–113:499–505CrossRefGoogle Scholar
  54. Medema RH, Kops GJ, Bos JL, Burgering BM (2000) AFX-like Forkhead transcription factors mediate cell cycle regulation by Ras and PKB through p27kip1. Nature 404:782–787PubMedCrossRefGoogle Scholar
  55. Meng Q, Yuan F, Goldberg ID, Rosen EM, Auborn K, Fan S (2000a) Indole-3-carbinol is a negative regulator of estrogen receptor α signalling in human tumor cells, J Nutr 130:2927–2931PubMedGoogle Scholar
  56. Meng Q, Goldberg ID, Rosen EM, Fan S (2000b) Inhibitory effect of indole-3-carbinol on invasion and migration in human breast cancer cells. Breast Cancer Res Treat 63:147–152PubMedCrossRefGoogle Scholar
  57. Meng Q, Qi M, Chen D-Z, Yuan R, Goldberg ID, Rosen EM, Auborn K, Fan S (2000c) Suppression of breast cancer invasion and migration by indole-3-carbinol:associ-ated with upregulation of BRCA1 and E-cadherin/catenin complexes, J Mol Med 78:155–165PubMedCrossRefGoogle Scholar
  58. Muise-Helmericks RC, Grimes HL, Bellacosa A, Malstrom SE, Tsichlis PN, Rosen N (1998) Cyclin D expression is controlled post-transcriptionally via a phos-phatidylinositol 3-kinase/Akt-dependent pathway. J Biol Chem 273:29864–29872PubMedCrossRefGoogle Scholar
  59. Nakamura N, Ramaswamy S, Vazquez F, Signoretti S, Loda M, Sellers WR (2000) Forkhead transcription factors are critical effectors of cell death and cell cycle arrest downstream of PTEN Mol Cell Biol 20:8969–8982PubMedCrossRefGoogle Scholar
  60. Nakatani K, Thompson DA, Barthel A, Sakaue H, Liu W, Weigel RJ, Roth RA (1999) Up-regulation of Akt3 in estrogen receptor-deficient breast cancers and androgen-independent prostate cancer cell lines. J Biol Chem 274:21528–21532PubMedCrossRefGoogle Scholar
  61. Ozes ON, Mayo LD, Gustin JA, Pfeffer SR, Pfeffer LM, Donner DB (1999) NF-κB activation by tumor necrosis factor requires the Akt serine-threonine kinase. Nature 401:82–85PubMedCrossRefGoogle Scholar
  62. Pahl HL (1999) Activators and target genes of Rel/NF-κB transcription factors. Oncogene 18:6853–6866PubMedCrossRefGoogle Scholar
  63. Plummer SM, Holloway KA, Manson MM, Munks RJL, Kaptein A, Farrow S, Howells L (1999) 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 18:6013–6020PubMedCrossRefGoogle Scholar
  64. Primiano T, Yu R, Kong A-N T (2001) Signal transduction events elicited by natural products that function as cancer chemopreventive agents. Pharm Biol 39:83–107CrossRefGoogle Scholar
  65. Rahman KMW, Aranha O, Glazyrin A, Chinni SR, Sarkar FH (2000) Translocation of Bax to mitochondria induces apoptoic cell death in indole-3-carbinol (I3C) treated breast cancer cells. Oncogene 19:5764–5771PubMedCrossRefGoogle Scholar
  66. Rayet B, Gelinas C (1999) Aberrant rel/nf-κb genes and activity in human cancer. Oncogene 18:6938–6947PubMedCrossRefGoogle Scholar
  67. Romashkova JA, Makarov SS (1999) NF-κB is a target of Akt in antiapoptotic PDGF signalling. Nature 401:86–90PubMedCrossRefGoogle Scholar
  68. Singh S, Aggarwal BB, (1995) Activation of transcription factor NF-kB is suppressed by curcumin (diferulolylmethane). J Biol Chem 270:24995–25000PubMedCrossRefGoogle Scholar
  69. Sizemore N, Leung S, Stark GR (1999) Activation of phosphotidylinositol-3-kinase in response to interleukin-1 leads to phosphorylation and activation of the NF-kB p65/Rel A subunit. Mol Cell Biol 19:4798–4805PubMedGoogle Scholar
  70. Schlessinger J (2000) Cell signalling by receptor tyrosine kinases. Cell 103:211–225PubMedCrossRefGoogle Scholar
  71. Waddick KG, Uckun FM (1999) Innovative treatment programs against cancer. II Nuclear factor κB (NF-κB) as a molecular target. Biochem Pharmacol 57:9–17PubMedCrossRefGoogle Scholar
  72. Weber JD, Hu W, Jefcoat SC, Raben DM, Baidassare JJ (1997) Ras-stimulated extracellular signal-related kinase 1 and RhoA activities coordinate platelet-derived growth factor-induced Gl progression through the independent regulation of cyclin D1 and p27kipl. J Biol Chem 272:32966–32971PubMedCrossRefGoogle Scholar
  73. Williams CS, Watson AJM, Sheng H, Helou R, Shao J, DuBois RN (2000) Celecoxib prevents tumor growth in vivo without toxicity to normal gut: lack of correlation between in vitro and in vivo models. Cancer Res 60:6045–6051PubMedGoogle Scholar
  74. Wiseman H (1994) Tamoxifen: molecular basis of use in cancer treatment and prevention. John Wiley and Sons, Chichester, UKGoogle Scholar
  75. Zhang Y, Kensler TW, Cho CG, Posner GH, Talalay P (1994) Anticarcinogenic activities of sulforaphane and structurally related synthetic norbornyl isothiocyanates. Proc Natl Acad Sci USA 91:3147–3150PubMedCrossRefGoogle Scholar
  76. Zhou BP, LiaoY, Xia W, Spohn B, Lee MH, Hung MC (2001) Cytoplasmic localization of p21Cip1/WAF1 by Akt-induced phosphorylation in HER-2/neu-overexpressing cells. Nature Cell Biol 3:245–252PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2003

Authors and Affiliations

  • M. M. Manson
  • L. M. Howells
  • E. A. Hudson

There are no affiliations available

Personalised recommendations