Phytochemistry Reviews

, Volume 11, Issue 2–3, pp 285–307 | Cite as

The chemopreventive role of dietary phytochemicals through gap junctional intercellular communication

  • Antonella Leone
  • Cristiano Longo
  • James E. Trosko


Dietary phytochemicals offer protection from oxidative damages and lower the risks of chronic diseases, by complementary and overlapping action mechanisms. These include antioxidant activity, regulation of gene expression and cell cycle, stimulation of the immune and hormonal systems and modulation of cell–cell communication. Gap-junction intercellular communication (GJIC) plays an important role in maintaining tissue homeostasis by allowing the intercellular exchange of ions and regulatory molecules associated with cell proliferation, differentiation and apoptosis, and by contributing to intracellular signaling. This mechanism is strictly regulated and abnormal GJIC can result in several pathological conditions. GJIC is deregulated in cancer cells and reversible GJIC inhibition is strongly related to the promotion phase of carcinogenesis, likely mediated by reactive oxygen species. Whereas, the reversible inhibition of GJIC is related to the promotion phase of carcinogenicity, enhancers of GJIC are expected to prevent cancer. Several dietary plant compounds demonstrated the ability to control GJIC at the epigenetic levels and to prevent GJIC down-regulation by tumor promoting compounds, thus preventing cancers. In this Commentary, a number of reported studies on several phytochemicals in dietary and medicinal plants, which were able to affect GJIC and their structural proteins, i.e., connexins, in different in vivo and in vitro systems, were examined. The growing evidence, on the involvement of plant-derived molecules in the modulation of GJIC and in understanding of the specific action mechanisms, might offer a new perspective of the protective and/or preventive effects of dietary phytochemicals, in addition to possible chemotherapeutic use.


Dietary phytochemicals Gap junction intercellular communication (GJIC) Cancer Antioxidants Epigenetic mechanisms 



Alpha-tocopherol, beta-carotene cancer prevention trial


Beta-carotene and retinol efficacy trial




Gap junction intercellular communication


Reactive oxygen species


Reactive oxygen intermediates


  1. Alarcòn de la Lastra C, Villegas I (2007) Resveratrol as an antioxidant and pro-oxidant agent: mechanisms and clinical implications. Biochem Soc T 35(5):1156–1160Google Scholar
  2. Al-Delaimy WK, van Kappel AL, Ferrari P, Slimani N, Steghens JP, Bingham S, Johansson I, Wallström P, Overvad K, Tjønneland A, Key TJ, Welch AA, Bueno-de-Mesquita HB, Peeters PH, Boeing H, Linseisen J, Clavel-Chapelon F, Guibout C, Navarro C, Quirós JR, Palli D, Celentano E, Trichopoulou A, Benetou V, Kaaks R, Riboli E (2004) Plasma levels of six carotenoids in nine European countries: report from the European prospective investigation into cancer and nutrition (EPIC). Public Health Nutr 7(6):713–722PubMedGoogle Scholar
  3. Alexopoulos H, Böttger A, Fischer S, Levin A, Wolf A, Fujisawa T, Hayakawa S, Gojobori T, Davies JA, David CN, Bacon JP (2004) Evolution of gap junctions: the missing link? Curr Biol 14:R879–R880PubMedGoogle Scholar
  4. Aust O, Ale-Agha N, Zhang L, Wollersen H, Sies H, Stahl W (2003) Lycopene oxidation product enhances gap junctional communication. Food Chem Toxicol 41:1399–1407PubMedGoogle Scholar
  5. Bao X, Altenberg GA, Reuss L (2004) Mechanism of regulation of the gap junction protein connexin 43 by protein kinase C-mediated phosphorylation. Am J Physiol Cell Physiol 286:C647–C654PubMedGoogle Scholar
  6. Baranova A, Ivanov D, Petrash N, Pestova A, Skoblov M, Kelmanson I, Shagin D, Nazarenko S, Geraymovych E, Litvin O, Tiunova A, Born TL, Usman N, Staroverov D, Lukyanov S, Panchin Y (2004) The mammalian pannexin family is homologous to the invertebrate innexin gap junction proteins. Genomics 83(4):706–716PubMedGoogle Scholar
  7. Beyer EC, Berthoud VM (2009) The family of connexin genes: In: Harris A, Locke D (eds) Connexins: a guide. Springer, New York, pp 3–26Google Scholar
  8. Block G, Patterson B, Subar A (1992) Fruit, vegetables, and cancer prevention. A review of the epidemiological evidence. Nutr Cancer 18:1–29PubMedGoogle Scholar
  9. Boassa D, Solan JL, Papas A, Thornton P, Lampe PD, Sosinsky GE (2010) Trafficking and recycling of the Connexin43 gap junction protein during mitosis. Traffic 11:1471–1486PubMedGoogle Scholar
  10. Boocock DJ, Faust GE, Patel KR, Schinas AM, Brown VA, Ducharme MP, Booth TD, Crowell JA, Perloff M, Gescher AJ, Steward WP, Brenner DE (2007) Phase I dose escalation pharmacokinetic study in healthy volunteers of resveratrol, a potential cancer chemopreventive agent. Cancer Epidem Biomar 16:1246–1252Google Scholar
  11. Brisset AC, Isakson BE, Kwak BR (2009) Connexins in vascular physiology and pathology. Antioxid Redox Sign 11(2):267–282Google Scholar
  12. Bruzzone R, White TW, Paul DL (1996) Connections with connexins: the molecular basis of direct intercellular signaling. Eur J Biochem 238:1–27PubMedGoogle Scholar
  13. Burkon A, Somoza V (2008) Quantification of free and protein-bound trans-resveratrol metabolites and identification of trans-resveratrol-C/O-conjugated diglucuronides—Two novel resveratrol metabolites in human plasma. Mol Nutr Food Res 52:549–557PubMedGoogle Scholar
  14. Cesen-Cummings K, Warner KA, Ruch RJ (1998) Role of protein kinase C in the deficient gap junctional intercellular communication of K-ras-transformed murine lung epithelial cells. Anticancer Res 18(6A):4343–4346Google Scholar
  15. Chalabi N, Delort L, Satih S, Déchelotte P, Bignon Y-J, Bernard-Gallon DJ (2007) Immunohistochemical expression of RARa, RARb, and Cx43 in breast tumor cell lines after treatment with lycopene and correlation with RT-QPCR. J Histochem Cytochem 55(9):877–883PubMedGoogle Scholar
  16. Chan R, Lok K, Woo J (2009) Prostate cancer and vegetable consumption. Mol Nutr Food Res 53:201–216PubMedGoogle Scholar
  17. Chaumontet C, Suschetet M, Honikman-Leban E, Krutovskikh VA, Berges R, Le Bon AM, Heberden C, Shahin MM, Yamasaki H, Martel P (1996) Lack of tumor-promoting effects of flavonoids: studies on rat liver preneoplastic foci and on in vivo and in vitro gap junctional intercellular communication. Nutr Cancer 26(3):251–263PubMedGoogle Scholar
  18. Chaumontet C, Droumaguet C, Bex V, Heberden C, Gaillard-Sanchez I, Martel P (1997) Flavonoids (apigenin, tangeretin) counteract tumor promoter-induced inhibition of intercellular communication of rat liver epithelial cells. Cancer Lett 114(1–2):207–210PubMedGoogle Scholar
  19. Choung Y-H, Choi SJ, Joo JS, Lee JB, Lee HK, Lee SJ (2011) Green tea prevents down-regulation of gap junction intercellular communication in human keratinocytes treated with PMA. Eur Arch Otorhinolaryngol 268:885–892PubMedGoogle Scholar
  20. Conklin CMJ, Bechberger JF, MacFabe D, Guthrie N, Kurowska EM, Naus CC (2007) Genistein and quercetin increase connexin43 and suppress growth of breast cancer cells. Carcinogenesis 28:93–100PubMedGoogle Scholar
  21. Cordain L, Miller JB, Eaton SB, Mann N, Holt SHA, Speth JD (2000) Plant-animal subsistence ratios and micronutrient energy estimates in worldwide huntergather diets and micronutrient energy estimates in worldwide huntergather diets. Am J Clin Nutr 71:682–692PubMedGoogle Scholar
  22. Cowan CG, Calwell EI, Young IS, McKillop DJ, Lamey PJ (1999) Antioxidant status of oral mucosal tissue and plasma levels in smokers and nonsmokers. J Oral Pathol Med 28:360–363PubMedGoogle Scholar
  23. Cronier L, Crespin S, Strale PO, Defamie N, Mesnil M (2009) Gap junctions and cancer: new functions for an old story. Antioxid Redox Signal 11(2):323–338PubMedGoogle Scholar
  24. Cruciani V, Mikalsen SO (2002) Connexins, gap junctional intercellular communication and kinases. Biol Cell 94(7–8):433–443PubMedGoogle Scholar
  25. Dresoti IE (2000) Antioxidant polyphenols in tea, cocoa, and wine. Nutrition 16:692–694Google Scholar
  26. Duffield-Lillico AJ, Begg CB (2004) Reflections on the landmark studies of b-carotene supplementation. J Natl Cancer Inst 96:1729–1731PubMedGoogle Scholar
  27. Duthie GG, Duthie SJ, Kyle JAM (2000) Plant polyphenols in cancer and heart disease: implications as nutritional antioxidants. Nutr Res Rev 13:79–106PubMedGoogle Scholar
  28. Engelmann NJ, Clinton SK, Erdman JE Jr (2011) Nutritional aspects of phytoene and phytofluene, carotenoid precursors to lycopene. Adv Nutr 2:51–61PubMedGoogle Scholar
  29. Evans WH, Martin PEM (2002) Gap junction structure and function. Mol Membr Biol 19:121–136PubMedGoogle Scholar
  30. Forbes PD, Urbach F, Davies RE (1979) Enhancement of experimental photocarcinogenesis by topical retinoic acid. Cancer Lett 7:85–90PubMedGoogle Scholar
  31. Ford NA, Elsen AC, Zuniga K, Lindshield BL, Erdman JW Jr (2011) Lycopene and apo-12′-lycopenal reduce cell proliferation and alter cell cycle progression in human prostate cancer cells. Nutr Cancer 63(2):256–263PubMedGoogle Scholar
  32. Fornelli F, Leone A, Verdesca I, Minervini F, Zacheo G (2007) The influence of lycopene on the proliferation of human breast cell line (MCF-7). Toxicol In Vitro 21(2):217–223PubMedGoogle Scholar
  33. Gill SR, Pop M, Deboy RT, Eckburg PB, Turnbaugh PJ, Samuel BS, Gordon JI, Relman DA, Fraser-Liggett CM, Nelson KE (2006) Metagenomic analysis of the human distal gut microbiome. Science 312:1355–1359PubMedGoogle Scholar
  34. Giovannucci E (2002) A review of epidemiologic studies of tomatoes, lycopene, and prostate. Cancer Exp Biol Med (Maywood) 227(10):852–859Google Scholar
  35. Goldberg DM, Yan J, Soleas GJ (2003) Absorption of three wine-related polyphenols in three different matrices by healthy subjects. Clin Biochem 36:79–87PubMedGoogle Scholar
  36. Goodenough DA, Paul DL (2009) Gap junctions. Cold Spring Harb Perspect Biol 1:a002576PubMedGoogle Scholar
  37. Goodman GE, Thornquist MD, Balmes J et al (2004) The beta-carotene and retinol efficacy trial: incidence of lung cancer and cardiovascular disease mortality during 6-year follow-up after stopping beta-carotene and retinol supplements. J Natl Cancer Inst 96:1743–1750PubMedGoogle Scholar
  38. Graf BA, Milbury PE, Blumberg JB (2005) Flavonols, flavones, flavanones, and human health: epidemiological evidence. J Med Food 8(3):281–290PubMedGoogle Scholar
  39. Guedes AC, Amaro HM, Malcata FX (2011) Microalgae as sources of carotenoids. Mar Drugs 9(4):625–644PubMedGoogle Scholar
  40. Hall EH, Crowe SE (2011) Environmental and lifestyle influences on disorders of the large and small intestine: implications for treatment. Dig Dis 29:249–254. doi: 10.1159/000323930 PubMedGoogle Scholar
  41. Heber D (2004) Phytochemicals beyond antioxidation. J Nutr 134(11):3175S–3176SPubMedGoogle Scholar
  42. Hehemann J-H, Correc G, Barbeyron T, Helbert W, Czjzek M, Michel G (2010) Transfer of carcohydrate-active enzymes from marine bacteria to Japanese gut microbiota. Nature 464:908–912PubMedGoogle Scholar
  43. Herve JC, Sarrouilhe D (2002) Modulation of junctional communication by phosphorylation: protein phosphatases, the missing link in the chain. Biol Cell 94:423–432PubMedGoogle Scholar
  44. Hesketh GG, Van Eyk JE, Tomaselli GF (2009) Mechanisms of gap junction traffic in health and disease. J Cardiovasc Pharmacol 54(4):263–272PubMedGoogle Scholar
  45. Holder JW, Elmore E, Barrett JC (1993) Gap junction function and cancer. Cancer Res 53(15):3475–3485PubMedGoogle Scholar
  46. Huang RP, Peng A, Hossain MZ, Fan Y, Jagdale A, Boynton AL (1999) Tumor promotion by hydrogen peroxide in rat liver epithelial cells. Carcinogenesis 20(3):485–492PubMedGoogle Scholar
  47. Huang RP, Peng A, Golard A, Hossain MZ, Huang R, Liu YG, Boynton AL (2001) Hydrogen peroxide promotes transformation of rat liver non-neoplastic epithelial cells through activation of epidermal growth factor receptor. Mol Carcinog 30:209–217PubMedGoogle Scholar
  48. Hunter DC, Greenwood J, Zhang J, Skinner MA (2011) Antioxidant and ‘natural protective’ properties of kiwifruit. Curr Top Med Chem 11(14):1811–1820PubMedGoogle Scholar
  49. Hwang J-W, Jung J-W, Lee Y-S, Kang K-S (2008) Indole-3-carbinol prevents H2O2-induced inhibition of gap junctional intercellular communication by inactivation of PKB/Akt. J Vet Med Sci 70(10):1057–1063PubMedGoogle Scholar
  50. Izzotti A, Calin GA, Steele VE, Cartiglia C, Longobardi M, Croce CM, De Flora S (2010) Chemoprevention of cigarette smoke-induced alterations of MicroRNA expression in rat lungs. Cancer Prev Res 3(1):62–72Google Scholar
  51. Jalil AM, Ismail A (2008) Polyphenols in cocoa and cocoa products: is there a link between antioxidant properties and health? Molecules 13(9):2190–2219PubMedGoogle Scholar
  52. Jiang JX, Gu S (2005) Gap junction- and hemichannel-independent actions of connexins. Biochim Biophys Acta 1711(2):208–214PubMedGoogle Scholar
  53. Jiang H, Shang X, Wu H, Huang G, Wang Y, Al-Holou S, Gautam SC, Chopp M (2010) Combination treatment with resveratrol and sulforaphane induces apoptosis in human U251 glioma cells. Neurochem Res 35(1):152–161PubMedGoogle Scholar
  54. Kalra EK (2003) Nutraceutical—definition and introduction. AAPS Pharm Sci 5(2):article 25. doi: 10.1208/ps050225
  55. Kang K-S, Trosko JE (2011) Stem cells in toxicology: Fundamental biology and practical considerations. Toxicol Sci 120:269–289Google Scholar
  56. Kang KS, Lee YS, Kim HS et al (2002) DI-(2-ethylhexyl) phthalate-induced cell proliferation is involved in the inhibition of gap junctional intercellular communication and blockage of apoptosis in mouse Sertoli cells. J Toxicol Environ Health A 65:447–459PubMedGoogle Scholar
  57. Kang NJ, Lee KM, Kim JH, Lee BK, Kwon JY, Lee KW, Lee HJ (2008) Inhibition of gap junctional intercellular communication by the green tea polyphenol (–)-epigallocatechin gallate in normal rat liver epithelial cells. J Agric Food Chem 56:10422–10427PubMedGoogle Scholar
  58. Kang H-G, Sang-Hee Jeong S-H, Cho J-H (2010) Antimutagenic and anticarcinogenic effect of methanol extracts of Petasites japonicus Maxim leaves. J Vet Sci 11(1):51–58PubMedGoogle Scholar
  59. Kau AL, Ahern PP, Griffin NW, Goodman AL, Gordon JI (2011) Human nutrition, the gut microbiome and the immune system. Nature 474:327–331PubMedGoogle Scholar
  60. Kaur M, Agarwal C, Agarwal R (2009) Anticancer and cancer chemopreventive potential of grape seed extract and other grape-based products. J Nutr 139(9):1806S–1812SPubMedGoogle Scholar
  61. Kelloff GJ, Lippman SM, Dannenberg AJ, Sigman CCHL, Reid BJ, Szabo E, Jordan VC, Spitz MR, Mills GB, Papadimitrakopoulou VA, Lotan R, Aggarwal BB, Bresalier RS, Banu Arun JK, Lu KH, Thomas ME, Rhodes HE, Brewer MA, Follen M, Shin DM, Parnes HL, Siegfried JM, Evans AA, Blot WJ, Chow W-H, Blount PL, Maley CC, Wang KK, Lam S, Lee JJ, Dubinett SM, Engstrom PF, Meyskens FL Jr, O’Shaughnessy J, Hawk ET, Levin B, Nelson WG, Hong WK (2006) Progress in chemoprevention drug development: the Promise of molecular biomarkers for prevention of intraepithelial neoplasia and cancer—A plan to move forward. Clin Cancer Res 12:3661–3697PubMedGoogle Scholar
  62. Key TJ, Schatzkin A, Willett WC, Allen NE, Spencer EA, Travis RC (2004) Diet, nutrition and the prevention of cancer. Public Health Nutr 7(1A):187–200Google Scholar
  63. Kim J-E, Kang T-C (2011) The P2X7 receptor–pannexin-1 complex decreases muscarinic acetylcholine receptor—mediated seizure susceptibility in mice. J Clin Invest 121(5):2037–2047. doi: 10.1172/JCI44818 Google Scholar
  64. Kim J-S, Ha T-Y, Ahn J, Kim H-K, Kim S (2009) Pterostilbene from Vitis coignetiae protect H2O2-induced inhibition of gap junctional intercellular communication in rat liver cell line. Food Chem Toxicol 47:404–409PubMedGoogle Scholar
  65. Kim J, Lee HJ, Lee KW (2010) Naturally occurring phytochemicals for the prevention of Alzheimer’s disease. J Neurochem 112(6):1415–1430PubMedGoogle Scholar
  66. King TJ, Bertram JS (2005) Connexins as targets for cancer chemoprevention and chemotherapy. Biochim Biophys Acta 1719(1–2):146–160PubMedGoogle Scholar
  67. Kobayashi H, Oikawa S, Hirakawa K, Kawanishi S (2004) Metal-mediated oxidative damage to cellular and isolated DNA by gallic acid, a metabolite of antioxidant propyl gallate. Mutat Res 558:111–120PubMedGoogle Scholar
  68. Krutovskikh V, Asamoto M, Takasuka N, Murakoshi M, Nishino H, Tsuda H (1997) Differential dose-dependent effects of alpha-, beta-carotenes and lycopene on gap-junctional intercellular communication in rat liver in vivo. Jpn J Cancer Res 88(12):1121–1124PubMedGoogle Scholar
  69. Laird DW (2005) Connexin phosphorylation as a regulatory event linked to gap junction internalization and degradation. Biochim Biophys Acta 1711:172–182PubMedGoogle Scholar
  70. Lampe PD, Lau AF (2004) The effects of connexin phosphorylation on gap junctional communication. Int J Biochem Cell Biol 36(7):1171–1186PubMedGoogle Scholar
  71. Lee KW, Lee HJ (2006) Biphasic effects of dietary antioxidants on oxidative stress-mediated carcinogenesis. Mech Ageing Dev 127:424–431PubMedGoogle Scholar
  72. Lee KW, Kim YJ, Lee HJ, Lee CY (2003) Cocoa has more phenolic phytochemicals and a higher antioxidant capacity than teas and red wine. J Agric Food Chem 51:7292–7295PubMedGoogle Scholar
  73. Lee KW, Chun KS, Lee JS, Kang KS, Surh YJ, Lee HJ (2004) Inhibition of cyclooxygenase-2 expression and restoration of gap junction intercellular communication in H-ras-transformed rat liver epithelial cells by caffeic acid phenethyl ester. Ann N Y Acad Sci 1030:501–507PubMedGoogle Scholar
  74. Lee DE, Kang NJ, Lee KM, Lee BK, Kim JH, Lee KW, Lee HJ (2010a) Cocoa polyphenols attenuate hydrogen peroxide-induced inhibition of gap-junction intercellular communication by blocking phosphorylation of connexin 43 via the MEK/ERK signaling pathway. J Nutr Biochem 21(8):680–686PubMedGoogle Scholar
  75. Lee DE, Shin BJ, Hur HJ, Kim JH, Kim J, Kang NJ, Kim DO, Lee CY, Lee KW, Lee HJ (2010b) Quercetin, the active phenolic component in kiwifruit, prevents hydrogen peroxide-induced inhibition of gap-junction intercellular communication Brit. J Nutr 104:164–170Google Scholar
  76. Leone S, Fiore M, Lauro MG, Pino S, Cornetta T, Cozzi R (2008) Resveratrol and X rays affect gap junction intercellular communications in human glioblastoma cells. Mol Carcinog 47:587–598PubMedGoogle Scholar
  77. Leone A, Zefferino R, Longo C, Leo L, Zacheo G (2010) Supercritical CO2-extracted tomato oleoresins enhance gap junction intercellular communications and recover from mercury chloride inhibition in keratinocytes. J Agric Food Chem 58:4769–4778PubMedGoogle Scholar
  78. Li Y, Tollefsbol TO (2010) Impact on DNA methylation in cancer prevention and therapy by bioactive dietary components. Curr Med Chem 17(20):2141–2151PubMedGoogle Scholar
  79. Linseisen J, Rohrmann S (2008) Biomarkers of dietary intake of flavonoids and phenolic acids for studying diet-cancer relationship in humans. Eur J Nutr 47(Suppl 2):60–68PubMedGoogle Scholar
  80. Liu RH (2004) Potential synergy of phytochemicals in cancer prevention: mechanism of action. J Nutr 134(12 Suppl):3479S–3485SPubMedGoogle Scholar
  81. Liu CL, Huang YS, Hosokawa M, Miyashita K, Hu ML (2009) Inhibition of proliferation of a hepatoma cell line by fucoxanthin in relation to cell cycle arrest and enhanced gap junctional intercellular communication. Chem Biol Interact 182(2–3):165–172PubMedGoogle Scholar
  82. Livny O, Kaplan I, Reifen R, Polak-Charcon S, Madar Z, Schwartz B (2002) Lycopene inhibits proliferation and enhances gap-junctional communication of KB-1 human oral tumor cells. J Nutr 132(12):3754–3759PubMedGoogle Scholar
  83. Loewenstein WR (1981) Junctional intercellular communication: the cell-to-cell membrane channel. Physiol Rev 61:829–913PubMedGoogle Scholar
  84. Mally A, Chipman JK (2002) Non-genotoxic carcinogens: early effects on gap junctions, cell proliferation and apoptosis in the rat. Toxicology 180:233–248PubMedGoogle Scholar
  85. Manach C, Scalbert A, Morand C, Rémésy C, Liliana Jiménez L (2004) Polyphenols: food sources and bioavailability. Am J Clin Nutr 79:727–747PubMedGoogle Scholar
  86. Mariani-Costantini A (2000) Natural and cultural influences on processes that shaped the eating habits of Western societies. Nutrition 16:483–486PubMedGoogle Scholar
  87. Martin PE, Blundell G, Ahmad S, Errington RJ, Evans WH (2001) Multiple pathways in the trafficking and assembly of connexin 26, 32 and 43 into gap junction intercellular communication channels. J Cell Sci 114(21):3845–3855PubMedGoogle Scholar
  88. Martin C, Butelli E, Petroni K, Tonelli C (2011) How can research on plants contribute to promoting human health? Plant Cell 23:1685–1699PubMedGoogle Scholar
  89. Maskarinec G (2009) Cancer protective properties of cocoa: a review of the epidemiologic evidence. Nutr Cancer 61(5):573–579PubMedGoogle Scholar
  90. Matesic DF, Rupp HL, Bonney WJ, Ruch RJ, Trosko JE (1994) Changes in gap junction permeability phosphorylation, and number mediated by phorbol ester and non-phorbol ester tumor promoters in rat liver epithelial cells”. Mol Carcinogen 10:226–236Google Scholar
  91. McCormack D, McFadden D (2011) Pterostilbene and cancer: current review. J Surg Res. doi: 10.1016/j.jss.2011.09.054 PubMedGoogle Scholar
  92. Mehta P, Bertram J, Loewenstein WR (1986) Growth inhibition of transformed cells correlates with their junctional communication with normal cells. Cell 44:187–196PubMedGoogle Scholar
  93. Mehta P, Bertram J, Loewenstein WR (1989) The actions of retinoids on cellular growth correlates with their actions on gap junctional communication. J Cell Biol 108:1053–1065PubMedGoogle Scholar
  94. Milton K (2000) Back to basics: why foods of wild primates have relevance for modern human health. Nutrition 16:480–483PubMedGoogle Scholar
  95. Moggs JG, Goodman JI, Trosko JE, Roberts RA (2004) Epigenetics and cancer: implications for drug discovery and safety assessment. Toxicol Appl Pharmacol 196:422–430PubMedGoogle Scholar
  96. Mograbi B, Corcelle E, Defamie N, Samson M, Nebout M, Segretain D, Fénichel P, Pointis G (2003) Aberrant connexin 43 endocytosis by the carcinogen lindane involves activation of the ERK/mitogen- activated protein kinase pathway. Carcinogenesis 24:1415–1423PubMedGoogle Scholar
  97. Motohashi N, Shirataki Y, Kawase M, Tani S, Sakagami H, Satoh K, Kurihara T, Nakashima H, Mucsi I, Varga A, Molnár J (2002) Cancer prevention and therapy with kiwifruit in Chinese folklore medicine: a study of kiwifruit extracts. J Ethnopharmacol 81(3):357–364PubMedGoogle Scholar
  98. Muegge BD, Kuczynski J, Knights D, Clemente JC, Gonzalez A, Fontana L, Henrissat B, Knight R, Gordon JI (2011) Diet drives convergence in gut microbiome functions across mammalian phylogeny and within humans. Science 332:970–974PubMedGoogle Scholar
  99. Musil LS, Goodenough DA (1991) Biochemical analysis of connexin43 intracellular transport, phosphorylation, and assembly into gap junctional plaques. J Cell Biol 115:1357–1374PubMedGoogle Scholar
  100. Na HK, Wilson MR, Kang KS, Chang CC, Grunberger D, Trosko JE (2000) Restoration of gap junctional intercellular communication by caffeic acid phenethyl ester (CAPE) in a ras-transformed rat liver epithelial cell line. Cancer Lett 157(1):31–38PubMedGoogle Scholar
  101. Nakamura Y, Yoshikawa N, Hiroki I, Sato K, Ohtsuki K, Chang C-C, Upham BL, Trosko JE (2005) Beta-sitosterol from psyllium seed husk (Plantago ovata Forsk) restores gap junctional intercellular communication in Ha-ras transfected rat liver cells. Nutr Cancer 51:218–225PubMedGoogle Scholar
  102. Naus CC, Laird DW (2010) Implications and challenges of connexin connections to cancer. Nat Rev Cancer 10:435–441PubMedGoogle Scholar
  103. Nielsen M, Ruch RJ, Vang O (2000) Resveratrol reverses tumor-promoter-induced inhibition of gap-junctional inter- cellular communication. Biochem Biophys Res Commun 275:804–809PubMedGoogle Scholar
  104. Nishino H, Murakoshi M, Mou XY, Wada S, Masuda M, Ohsaka Y, Satomi Y, Jinno K (2005) Cancer prevention by phytochemicals. Oncology 69(Suppl 1):38–40PubMedGoogle Scholar
  105. Obrenovich ME, Li Y, Parvathaneni K, Yendluri BB, Palacios HH, Leszek J, Aliev G (2011) Antioxidants in health, disease and aging. CNS Neurol Disord-Dr 10(2):192–207Google Scholar
  106. Okarter N, Liu RH (2010) Health benefits of whole grain phytochemicals. Crit Rev Food Sci Nutr 50(3):193–208PubMedGoogle Scholar
  107. Omori Y, Krutovskikh V, Mironov N, Tsuda H, Yamasaki H (1996) Cx32 gene mutation in a chemically induced rat liver tumour. Carcinogenesis 17:2077–2080PubMedGoogle Scholar
  108. Pahujaa M, Anikin M, Goldberg GS (2007) Phosphorylation of connexin43 induced by Src: regulation of gap junctional communication between transformed cells. Exp Cell Res 313(20):4083–4090PubMedGoogle Scholar
  109. Palozza P, Parrone N, Catalano A, Simone R (2010) Tomato lycopene and inflammatory cascade: basic interactions and clinical implications. Curr Med Chem 17:2547–2563PubMedGoogle Scholar
  110. Palozza P, Simone RE, Catalano A, Mele MC (2011) Tomato lycopene and lung cancer prevention: from experimental to human studies. Cancers 3:2333–2357. doi: 10.3390/cancers3022333 Google Scholar
  111. Panchin YV (2005) Evolution of gap junction proteins-the pannexin alternative. J Exp Biol 208:1415–1419PubMedGoogle Scholar
  112. Paoloni-Giacobino A, Grimble R, Pichard C (2003) Genetics and nutrition. Clin Nutr 22:429–435PubMedGoogle Scholar
  113. Phelan P (2005) Innexins: members of an evolutionarily conserved family of gap-junction proteins. Biochim Biophys Acta 1711(2):225–245PubMedGoogle Scholar
  114. Phelan P, Starich TA (2001) Innexins get into the gap. BioEssays 23(5):388–396PubMedGoogle Scholar
  115. Pointis G, Fiorini C, Gilleron J, Carette D, Segretain D (2007) Connexins as precocious markers and molecular targets for chemical and pharmacological agents in carcinogenesis. Curr Med Chem 14:2288–2303PubMedGoogle Scholar
  116. Richard G (2001) Connexin disorders of the skin. Adv Dermatol 17:243–277PubMedGoogle Scholar
  117. Ried K, Fakler P (2011) Protective effect of lycopene on serum cholesterol and blood pressure: meta-analyses of intervention trials. Maturitas 68:299–310PubMedGoogle Scholar
  118. Rivedal E, Leithe E (2005) Connexin43 synthesis, phosphorylation, and degradation in regulation of transient inhibition of gap junction intercellular communication by the phorbol ester TPA in rat liver epithelial cells. Exp Cell Res 302:143–152PubMedGoogle Scholar
  119. Roger C, Mograbi B, Chevallier D, Michiels JF, Tanaka H, Segretain D, Pointis G, Fenichel P (2004) Disrupted traffic of connexin 43 in human testicular seminoma cells: overexpression of Cx43 induces membrane location and cell proliferation decrease. J Pathol 202:241–246PubMedGoogle Scholar
  120. Rose B, Mehta PP, Loewenstein WR (1993) Gap-junction protein gene suppresses tumorigenicity. Carcinogenesis 14:1073–1075PubMedGoogle Scholar
  121. Ross SA (2010) Evidence for the relationship between diet and cancer. Exp Oncol 32(3):137–142PubMedGoogle Scholar
  122. Ruch RJ, Cheng SJ, Klaunig JE (1989) Prevention of cytotoxicity and inhibition of intercellular communication by antioxidant catechins isolated from Chinese green tea. Carcinogenesis 10:1003–1008PubMedGoogle Scholar
  123. Ruch RJ, Madhukar BV, Trosko JE, Klaunig JE (1993) Reversal of ras-induced inhibition of gap-junctional intercellular communication, transformation, and tumorigenesis by lovastatin. Mol Carcinog 7(1):50–59PubMedGoogle Scholar
  124. Sabarinathan D, Vanisree AJ (2010) Naringenin, a flavanone alters the tumorigenic features of C6 glioma cells. Biomed Pharmacother. doi: 10.1016/j.biopha.2010.06.010 PubMedGoogle Scholar
  125. Sai K, Kanno J, Hasegawa R, Trosko JE, Inoue T (2000) Prevention of the down-regulation of gap junctional intercellular communication by green tea in the liver of mice fed pentachlorophenol. Carcinogenesis 21(9):1671–1676PubMedGoogle Scholar
  126. Sai K, Kang KS, Hirose A, Hasegawa R, Trosko JE, Inoue T (2001) Inhibition of apoptosis by pentachlorophenol in v-myc-transfected rat liver epithelial cells: relation to down-regulation of gap junctional intercellular communication. Cancer Lett 173(2):163–174PubMedGoogle Scholar
  127. Shakibaei M, Harikumar KB, Aggarwal BB (2009) Resveratrol addiction: to die or not to die. Mol Nutr Food Res 53:115–128PubMedGoogle Scholar
  128. Shen J, Wang LH, Zheng LR, Zhu JH, Hu SJ (2010) Lovastatin inhibits gap junctional communication in cultured aortic smooth muscle cells. J Cardiovasc Pharm T 15(3):296–302Google Scholar
  129. Shuin T, Nishimura R, Noda K, Umeda M, Ono T (1983) Concentration-dependent differential effect of retinoic acid on intercellular metabolic cooperation. Gann 74:100–105PubMedGoogle Scholar
  130. Shulzhenko N, Morgun A, Hsiao W, Battle M, Yao M, Gavrilova O, Orandle M, Mayer L, Macpherson AJ, McCoy KD, Fraser-Liggett C, Matzinger P (2011) Crosstalk between B lymphocytes, microbiota and the intestinal epithelium governs immunity versus metabolism in the gut. Nat Med 17:1585–1590PubMedGoogle Scholar
  131. Simek J, Churko J, Shao Q, Laird DW (2009) Cx43 has distinct mobility within plasma-membrane domains, indicative of progressive formation of gap-junction plaques. J Cell Sci 122:554–562PubMedGoogle Scholar
  132. Singh P, Goyal GK (2008) Dietary lycopene: its properties and anticarcinogenic effects. Compr Rev Food Sci F 7(3):255–270Google Scholar
  133. Solan JL, Lampe PD (2009) Connexin43 phosphorylation: structural changes and biological effects. Biochem J 419(2):261–272PubMedGoogle Scholar
  134. Sosinsky GE, Boassa D, Dermietzel R, Duffy HS, Laird DW, MacVicar B, Naus CC, Penuela S, Scemes E, Spray DC, Thompson RJ, Zhao HB, Dahl G (2011) Pannexin channels are not gap junction hemichannels. Channels 5(3):193–197PubMedGoogle Scholar
  135. Stahl W, von Laar J, Martin HD, Emmerich T, Sies H (2000) Stimulation of gap junctional communication: comparison of acyclo- retinoic acid and lycopene. Arch Biochem Biophys 373(1):271–274PubMedGoogle Scholar
  136. Surh YJ (1999) Molecular mechanisms of chemopreventive effects of selected dietary and medicinal phenolic substances. Mutat Res 428:305–327PubMedGoogle Scholar
  137. Takahashi H, Nomata K, Mori K, Matsuo M, Miyaguchi T, Noguchi M, Kanetake H (2004) The preventive effect of green tea on the gap junction intercellular communication in renal epithelial cells treated with a renal carcinogen. Anticancer Res 24(6):3757–3762PubMedGoogle Scholar
  138. Teaford MF, Ungar PS (2000) Diet and the evolution of the earliest human ancestors. Proc Natl Acad Sci USA 97:13506–13511PubMedGoogle Scholar
  139. Temme A, Buchmann A, Gabriel HD, Nelles E, Schwarz M, Willecke K (1997) High incidence of spontaneous and chemically-induced liver tumors in mice deficient for connexin32. Curr Biol 7:713–716PubMedGoogle Scholar
  140. Trosko JE (2003) The role of stem cells and gap junctional intercellular communication in carcinogenesis. J Biochem Mol Biol 36:43–48PubMedGoogle Scholar
  141. Trosko JE (2007a) Stem cells and cell–cell communication in the understanding of the role of diet and nutrients in human diseases. J Food Hygiene Safety 22(1):1–14Google Scholar
  142. Trosko JE (2007b) Gap junctional intercellular communication as a biological “Rosetta stone” in understanding, in a systems biological manner, stem cell behavior, mechanisms of epigenetic toxicology, chemoprevention and chemotherapy. J Membr Biol 218(1–3):93–100Google Scholar
  143. Trosko JE (2008) Human adult stem cells as targets for cancer stem cells: evolution: Oct- 4 gene and cell–cell communication. In: Dittmar T, Zaenkar K (eds) Stem cells and cancer. Nova Science Publishers, New York, pp 147–187Google Scholar
  144. Trosko JE (2009) Cancer stem cells and cancer non-stem cells: from adult stem cells or from re-programming of differentiated somatic cells. Vet Pathol 46(2):176–193PubMedGoogle Scholar
  145. Trosko JE (2011) The gap junction as a “Biological Rosetta Stone”: implications of evolution, stem cells to homeostatic regulation of health and disease in the Barker hypothesis. J Cell Commun Signal 5(1):53–66PubMedGoogle Scholar
  146. Trosko JE (in press) Prenatal Epigenetic influences on acute and chronic diseases later in life, such as cancer: global health crises resulting from a collision of biological and cultural evolution. J Food Sci NutritGoogle Scholar
  147. Trosko JE, Chang CC (2000) Modulation of cell–cell communication in the cause and chemoprevention/chemotherapy of cancer. BioFactors 12(1–4):259–263PubMedGoogle Scholar
  148. Trosko JE, Chang CC (2001) Mechanism of up-regulated gap junctional intercellular communication during chemoprevention and chemotherapy of cancer. Mutat Res 480–481:219–229PubMedGoogle Scholar
  149. Trosko JE, Ruch RJ (1998) Cell-cell communication in carcinogenesis. Front Biosci 3:208–236Google Scholar
  150. Trosko JE, Ruch RJ (2002) Gap junctions as therapeutic targets. Curr Drug Targets 3(6):465–482PubMedGoogle Scholar
  151. Trosko JE, Tai MH (2006) Adult stem cell theory of the multistage, multi- mechanism theory of carcinogenesis: role of inflammation on the promotion of initiated stem cells. In: Dittmar T, Zaenker KS, Schmidt A (eds) Infection and inflammation: impacts on oncogenesis. Contrib Microbiol. Basel, Karger, vol 13, pp 45–65. doi: 10.1159/000092965
  152. Trosko JE, Chang CC, Upham B, Wilson M (1998) Epigenetic toxicology as toxicant-induced changes in intracellular signalling leading to altered gap junctional intercellular communication. Toxicol Lett 102–103:71–78PubMedGoogle Scholar
  153. Trosko JE, Chang CC, Wilson MR, Upham B, Hayashi T, Wade M (2000) Gap junctions and the regulation of cellular functions of stem cells during development and differentiation. Methods 20(2):245–264PubMedGoogle Scholar
  154. Turnbaugh PJ, Ridaura VK, Faith JJ, Rey FE, Knight R, Gordon JI (2009) The effect of diet on the human gut microbiome: a metagenomic analysis in humanized gnotobiotic mice. Sci Transl Med 1(6): 70–79Google Scholar
  155. Unwin PN, Zampighi G (1980) Structure of the junction between communicating cells. Nature 283(5747):545–549PubMedGoogle Scholar
  156. Upham BL, Trosko JE (2009) Carcinogenic tumor promotion, induced oxidative stress signaling, modulated gap junction function and altered gene expression. Antioxid Redox Signal 11:297–308PubMedGoogle Scholar
  157. Upham BL, Weis LM, Trosko JE (1998) Modulated gap junctional intercellular communication as a biomarker of PAH epigenetic toxicity: structure-function relationship. Environ Health Perspect 106(Suppl. 4):975–981PubMedGoogle Scholar
  158. Upham BL, Guzvic M, Scott J, Carbone JM, Blaha L, Coe C, Li LL, Rummel AL, Trosko JE (2007) Inhibition of gap junctional intercellular communication and activation of mitogen-activation protein kinase by tumor-promoting organic peroxides and protection by resveratrol. Nutr Cancer 57(1):38–47PubMedGoogle Scholar
  159. Vainio H, Weiderpass E (2006) Fruit and vegetables in cancer prevention. Nutr Cancer 54(1):111–142PubMedGoogle Scholar
  160. van der Pols JC, Heinen MM, Hughes MC, Ibiebele TI, Marks GC, Green AC (2009) Serum antioxidants and skin cancer risk: an 8-year community-based follow-up study. Cancer Epidemiol Biomarkers Prev 18(4):1167–1173PubMedGoogle Scholar
  161. Vang O, Ahmad N, Baile CA, Baur JA, Brown K, Csiszar A, Das DK, Delmas D, Gottfried C, Lin HY, Ma QY, Mukhopadhyay P, Nalini N, Pezzuto JM, Richard T, Shukla Y, Surh YJ, Szekeres T, Szkudelski T, Walle T, Wu JM (2011) What is new for an old molecule? Systematic review and recommendations on the use of resveratrol. PLoS ONE 6(6):e19881PubMedGoogle Scholar
  162. Vine AL, Bertram JS (2002) Cancer chemoprevention by connexins. Cancer Metastasis Rev 21(3–4):199–216PubMedGoogle Scholar
  163. Vinken M, Vanhaecke T, Papeleu P, Snykers S, Henkens T, Rogiers V (2006) Connexins and their channels in cell growth and cell death. Cell Signal 18(5):592–600PubMedGoogle Scholar
  164. Vinken M, De Rop E, Decrock E, De Vuyst E, Leybaert L, Vanhaecke T, Rogiers V (2009) Epigenetic regulation of gap junctional intercellular communication: more than a way to keep cells quiet? Biochim Biophys Acta 1795(1):53–61PubMedGoogle Scholar
  165. Vinken M, Vanhaecke T, Rogiers V (2010) Emerging roles of connexin hemichannels in gastrointestinal and liver pathophysiology. World J Gastrointest Pathophysiol 1(4):115–117PubMedGoogle Scholar
  166. Vinken M, Decrock E, De Vuyst E, Ponsaerts R, D’hondt C, Bultynck G, Ceelen L, Vanhaecke T, Leybaert L, Rogiers V (2011) Connexins: sensors and regulators of cell cycling. Biochim Biophys Acta 1815(1):13–25PubMedGoogle Scholar
  167. Wei CJ, Xu X, Lo CW (2004) Connexins and cell signaling in development and disease. Ann Rev Cell Dev Biol 20:811–836Google Scholar
  168. Weisburger JH (2001) Chemopreventive effects of cocoa polyphenols on chronic diseases. Exp Biol Med (Maywood) 226(10):891–897Google Scholar
  169. Welsch CW, Goodrich-Smith M, Brown CK, Crowe N (1981) Enhance by retinyl Acetate of hormone induced mammary tumorigenesis in female GR/A mice. J Natl Cancer Inst 67(4):935–938PubMedGoogle Scholar
  170. Weng JR, Tsai CH, Kulp SK, Chen CS (2008) Indole-3-carbinol as a chemopreventive and anti-cancer agent. Cancer Lett 262(2):153–163PubMedGoogle Scholar
  171. Woodworth HL, McCaskey SJ, Duriancik DM, Clinthorne JF, Langohr IM, Gardner EM, Fenton JI (2010) Dietary fish oil alters T lymphocyte cell populations and exacerbates disease in a mouse model of inflammatory colitis. Cancer Res 70(20):7960–7969PubMedGoogle Scholar
  172. Wu GD, Chen J, Hoffmann C, Bittinger K, Chen Y-Y, Keilbaugh SA, Bewtra M, Knights D, Walters WA, Knight R, Sinha R, Gilroy E, Gupta K, Baldassano R, Nessel L, Li H, Bushman FD, Lewis JD (2011) Linking long-term dietary patterns with gut microbial enterotypes. Science 334(6052):105–108PubMedGoogle Scholar
  173. Yamasaki H (1995) Non-genotoxic mechanisms of carcinogenesis: studies of cell transformation and gap junctional intercellular communication. Toxicol Lett 77(1–3):55–61PubMedGoogle Scholar
  174. Yamasaki H, Enomoto T (1985) Role of intercellular communication in BALB/c 3T3 cell transformation. Carcinog Compr Surv 9:179–194PubMedGoogle Scholar
  175. Yamasaki H, Naus CC (1996) Role of connexin genes in growth control. Carcinogenesis 17(6):1199–1213PubMedGoogle Scholar
  176. Yamasaki H, Hollstein M, Mesnil M, Martel N, Aguelon AM (1987) Selective lack of intercellular communication between transformed and nontransformed cells as a common property of chemical and oncogene transformation of BALB/c 3T3 cells. Cancer Res 47:5658–5664PubMedGoogle Scholar
  177. Yamasaki H, Krutovskikh V, Mesnil M, Columbano A, Tsuda H, Ito N (1993) Gap junctional intercellular communication and cell proliferation during rat liver carcinogenesis. Environ Health Perspect 101(Suppl 5):191–197PubMedGoogle Scholar
  178. Yan F, Tian XM, Ma XD (2006) Effects of resveratrol on growth inhibition and gap-junctional intercellular communication of HepG2 cells. Nan Fang Yi Ke Da Xue Xue Bao 26(7):963–966PubMedGoogle Scholar
  179. Yotti LP, Chang CC, Trosko JE (1979) Elimination of metabolic cooperation in Chinese hamster cells by a tumor promoter. Science 206(4422):1089–1091PubMedGoogle Scholar
  180. Yu L, Zhao Y, Fan Y, Wang M, Xu S, Fu G (2010) Epigallocatechin-3 gallate, a green tea catechin, attenuated the downregulation of the cardiac gap junction induced by high glucose in neonatal rat cardiomyocytes. Cell Physiol Biochem 26(3):403–412PubMedGoogle Scholar
  181. Zamin LL, Filippi-Chiela EC, Dillenburg-Pilla P, Horn F, Salbego C, Lenz G (2009) Resveratrol and quercetin cooperate to induce senescence-like growth arrest in C6 rat glioma cells. Cancer Sci 100(9):1655–1662PubMedGoogle Scholar
  182. Zefferino R, Leone A, Piccaluga S, Cincione R, Ambrosi L (2008) Mercury modulates interplay between IL-1β, TNF-α, and gap junctional intercellular communication in keratinocytes: mitigation by lycopene. J Immunotoxicol 5(4):353–360PubMedGoogle Scholar
  183. Zhang LX, Cooney RV, Bertram JS (1991) Carotenoids enhance gap junctional communication and inhibit lipid peroxidation in C3H/10T1/2 cells: relationship to their cancer chemopreventive action. Carcinogenesis 12(11):2109–2114PubMedGoogle Scholar
  184. Zhang Y-W, Dou D-Q, Zhang L, Chen Y-J, Yao X-S (2001) Effects of ginsenosides from Panax ginseng on cell-to-cell communication function mediated by gap junctions. Planta Med 67(5):417–422. doi: 10.1055/s-2001-15816 PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2012

Authors and Affiliations

  • Antonella Leone
    • 1
  • Cristiano Longo
    • 1
  • James E. Trosko
    • 2
  1. 1.Institute of Science of Food Production, Unit of Lecce (ISPA-Lecce)National Research Council (CNR)LecceItaly
  2. 2.Department of Pediatrics and Human DevelopmentFood Safety and Toxicology Center, Center for Integrative Toxicology, Michigan State UniversityEast LansingUSA

Personalised recommendations