DOI QR코드

DOI QR Code

Anti-Proliferative Effect of Ethanol on Normal and Cancer Cells

정상세포와 암세포의 증식 억제에 대한 에탄올의 영향

  • Oh, Myung-Ju (Division of Clinical Trials Management, Bureau of Risk Prevention Policy, Korea Food and Drug Administration) ;
  • Kim, Ji-Hyun (Department of Nanomedical Engineering, Pusan National University) ;
  • Park, Su-Hyun (Department of Nanomedical Engineering, Pusan National University) ;
  • Jeong, Young-Hwa (Department of Nanomedical Engineering, Pusan National University) ;
  • Wang, Kun (Department of Animal Sciences, Pusan National University) ;
  • Cho, Byung-Wook (Department of Animal Sciences, Pusan National University) ;
  • Jhun, Byung-H. (Department of Nanomedical Engineering, Pusan National University)
  • 오명주 (식품의약청 임상시험관리부) ;
  • 김지현 (부산대학교 나노과학기술대학 나노메디컬공학과) ;
  • 박수현 (부산대학교 나노과학기술대학 나노메디컬공학과) ;
  • 정영화 (부산대학교 나노과학기술대학 나노메디컬공학과) ;
  • 왕쿤 (부산대학교 생명자원과학대학 동물자원학과) ;
  • 조병욱 (부산대학교 생명자원과학대학 동물자원학과) ;
  • 전병학 (부산대학교 나노과학기술대학 나노메디컬공학과)
  • Received : 2012.02.17
  • Accepted : 2012.03.22
  • Published : 2012.04.30

Abstract

Ethanol is known as being carcinogenic to humans. In addition, the anti-proliferative effects of ethanol have been described for a variety of tissues and cells. In this study, we investigated the anti-proliferative effects of ethanol on various cancer cells, particularly on oncogenic $ras$-transformed or-injected cells. Ethanol treatment inhibited the cell proliferation of normal control cells, but did not suppress the proliferation of various cancer cells and oncogenic $ras$-transformed cells. Furthermore, ethanol treatment did not interfere with DNA synthesis, which was induced by microinjecting the oncogenic $H-Ras^{V12}$ protein. The anti-proliferative effect of ethanol was rescued by antioxidants, such as $N$-acetylcysteine and 4-methlpyrazole. These results suggest that ethanol cytotoxicity is exerted through free radical formation, and that the anti-proliferative action site of ethanol cytotoxicity either lies upstream, or is independent of Ras.

에탄올은 사람에 대한 발암물질로 잘 알려져 있다. 또한 여러 조직이나 세포에서의 에탄올에 의한 세포증식억제효과도 잘 알려져 있다. 본 연구에서는 여러 암세포에서 에탄올에 의한 세포증식억제 효과를 조사하였는데 특히 발암원성 $ras$로 형질전환되거나 미세주입된 세포에서의 영향을 조사하였다. 에탄올은 여러 정상세포들의 증식을 억제하였다. 반면에 여러 암세포나 발암원성 Ras에 의한 세포증식은 억제하지 못 하였다. 또한 발암원성 단백질의 세포내 미세주사에 의한 DNA합성 유도도 에탄올에 의해 억제 되지 않았다. 이러한 에탄올의 세포증식억제 효과는 $N$-acetylcysteine이나 4-methylpyrazole과 같은 항산화제에 의해 제거되었다. 이러한 실험 결과는 에탄올에 의한 세포증식억제 효과는 Ras단백질의 upstream에 있거나 또는 Ras와 독립적으로 작용하며, 활성산소 형성과 밀접한 관계가 있다는 것을 알려준다.

Keywords

References

  1. Baan, R., Straif, K., Grosse, Y., Secretan, B., el Ghissassi, F., Bouvard, V., Altieri, A. and Cogliano, V. 2007. Carcinogenicity of alcoholic beverages. Lancet Oncol. 8, 292-293. https://doi.org/10.1016/S1470-2045(07)70099-2
  2. Boffetta, P. and Hashibe, M. 2006. Alcohol and cancer. Lancet Oncol. 7, 149-156. https://doi.org/10.1016/S1470-2045(06)70577-0
  3. Brennan, P., Lewis, S., Hashibe, M., Bell, D. A., Boffetta, P., Bouchardy, C., Caporaso, N., Chen, C., Coutelle, C., Diehl, S. R., Hayes, R. B. Olshan, A. F., Schwartz, S. M., Sturgis, E. M., Wei, Q. A., Zavras, I. and Benhamou, S. 2004. Pooled analysis of alcohol dehydrogenase genotypes and head and neck cancer: a HuGE review. Am. J. Epidemiol. 159, 1-16. https://doi.org/10.1093/aje/kwh003
  4. Chavez, P. R., Lian, F., Chung, J., Liu, C. S., Paiva, A., Seitz, H. K. and Wang, X. D. 2011. Long-term ethanol consumption promotes hepatic tumorigenesis but impairs normal hepatocyte proliferation in rats. J. Nutr. 141, 1049-1055. https://doi.org/10.3945/jn.110.136531
  5. Chen, G., Colombo, L. L., Lopez, M. C. and Watson, R. R. 1996. Effect of ethanol and cocaine treatment of the immune system of v-Ha-ras-transgenic mice. Int. J. Immunopharmacol. 18, 251-258. https://doi.org/10.1016/0192-0561(96)84504-8
  6. Crous-Bou, M., Porta, M., López, T., Jariod, M., Malats, N., Morales, E. Guarner, L., Rifà, J. and Carrato, A. 2009. Real FX; PANKRAS II Study Group. Lifetime history of alcohol consumption and K-ras mutations in pancreatic ductal adenocarcinoma. Environ. Mol. Mutagen. 50, 421-430. https://doi.org/10.1002/em.20483
  7. Derdak, Z., Lang, C. H., Villegas, K. A., Tong, M. N., Mark, M., de la Monte, S. M. and Wands, J. R. 2011. Activation of p53 enhances apoptosis and insulin resistance in a rat model of alcoholic liver disease. J. Hepatol. 54, 164-172.
  8. Fan, J., Edsen-Moore, M. R., Turner, L. E., Cook, R. T., Legge, K. L., Waldschmidt, T. J. and Schlueter, A. J. 2011. Mechanisms by which chronic ethanol feeding limits the ability of dendritic cells to stimulate T-cell proliferation. Alcohol Clin. Exp. Res. 35, 47-59. https://doi.org/10.1111/j.1530-0277.2010.01321.x
  9. Hipp, J. A., Hipp, J. D., Atala, A. and Soker, S. 2010. Ethanol alters the osteogenic differentiation of amniotic fluid-derived stem cells. Alcohol Clin. Exp. Res. 34, 1714-1722. https://doi.org/10.1111/j.1530-0277.2010.01258.x
  10. Hoek, J. B. and Pastorino, J. G. 2002. Ethanol, oxidative stress, and cytokine induced liver cell injury. Alcohol 27, 63-68. https://doi.org/10.1016/S0741-8329(02)00215-X
  11. International Agency for Research on Cancer. 1988. Alcohol drinking. IARC monographs on the evaluation of carcinogenic risks to humans. Vol. 44, Lyon: IARC.
  12. Jeannot, E., Pogribny, I. P., Beland, F. A. and Rusyn, I. 2011. Chronic administration of ethanol leads to an increased incidence of hepatocellular adenoma by promoting H-ras-mutated cells. Cancer Lett. 301, 161-167. https://doi.org/10.1016/j.canlet.2010.11.010
  13. Jhun, B. H., Meinkoth, J. M., Leitner, J. W., Draznin, B. and Olefsky, J. M. 1994. Insulin and insulin-like growth factor-I signal transduction requires p21ras. J. Biol. Chem. 269, 5699-5704.
  14. LeBel, C. P., Ischiropoulos, H. and Bondy, S. C. 1992. Evaluation of the probe 2',7'-dichlorofluorescin as an indicator of reactive oxygen species formation and oxidative stress. Chem. Res. Toxicol. 5, 227-231. https://doi.org/10.1021/tx00026a012
  15. Molina, P. E., Hoek, H. B., Nelson, S., Guidot, D. M., Lang, C. H., Wands, J. R. and Crawford, J. M. 2003. Mechanisms of alcohol induced tissue injury. Alcohol Clin. Exp. Res. 27, 563-575. https://doi.org/10.1097/01.ALC.0000057946.57330.F7
  16. Morris, S. A., Eaves, D. W., Smith, A. R. and Nixon, K. 2010. Alcohol inhibition of neurogenesis: a mechanism of hippocampal neurodegeneration in an adolescent alcohol abuse model. Hippocampus 20, 596-607.
  17. Morrow, D., Cullen, J. P., Liu, W., Cahill, P. A. and Redmond, E. M. 2010. Alcohol inhibits smooth muscle cell proliferation via regulation of the Notch signaling pathway. Arterioscler. Thromb. Vasc. Biol. 30, 2597-2603. https://doi.org/10.1161/ATVBAHA.110.215681
  18. Ness, K. J., Fan, J., Wilke, W. W., Coleman, R. A., Cook, R. T. and Schlueter, A. J. 2008. Chronic ethanol consumption decreases murine Langerhans cell numbers and delays migration of Langerhans cells as well as dermal dendritic cells. Alcohol Clin. Exp. Res. 2, 657-668.
  19. Oh, M. J., van Agthoven, T., Choi, J. E., Jeong, Y. J., Chung, Y. H., Kim, C. M. and Jhun, B. H. 2008. BCAR3 regulates EGF-induced DNA synthesis in normal human breast MCF-12A cells. Biochem. Biophys. Res. Commun. 375, 430-434. https://doi.org/10.1016/j.bbrc.2008.08.040
  20. Pylayeva-Gupta, Y., Grabocka, E. and Bar-Sagi, D. 2011. RAS oncogenes: weaving a tumorigenic web. Nat. Rev. Cancer 11, 761-774. https://doi.org/10.1038/nrc3106
  21. Rehm, J., Room, R., Monteiro, M., Gmel, G., Graham, K., Rehn, N., Sempos, C. T., Frick, U. and Jernigan, D. 2004. Alcohol use. pp. 960-1108, In Ezzati, M., A. Lopez, A. Rodgers, and C. Murray (eds.), Comparative Quantification of Health Risks. Global and Regional Burden of Disease Attributable to Selected Major Risk Factors. WHO, Geneva.
  22. Resnicoff, M., Sell, C., Ambrose, D., Baserga, R. and Rubin, R. 1993. Ethanol inhibits the autophosphorylation of the insulin-like growth factor 1 (IGF-1) receptor and IGF-1-mediated proliferation of 3T3 cells. J. Biol. Chem. 268, 21777-21782.
  23. Trachootham, D., Zhou, Y., Zhang, H., Demizu, Y., Chen, Z., Pelicano, H., Chiao, P. J., Achanta, G., Arlinghaus, R. B., Liu, J. and Huang, P. 2006. Selective killing of oncogenically transformed cells through a ROS-mediated mechanism by beta-phenylethyl isothiocyanate. Cancer Cell. 10, 241-252. https://doi.org/10.1016/j.ccr.2006.08.009
  24. Wands, J. R., Carter, E. A., Bucher, N. L. R. and Isselbacher, K. J. 1980. Effect of acute and chronic ethanol intoxication on hepatic regeneration. Adv. Exp. Med. Biol. 132, 663-670.
  25. Wang, H., Zhou, H., Chervenak, R., Moscatello, K. M., Brunson, L. E. and Chervenak, D. C. 2009. Wolcott RM. Ethanol exhibits specificity in its effects on differentiation of hematopoietic progenitors. Cell Immunol. 255, 1-7. https://doi.org/10.1016/j.cellimm.2008.08.008
  26. Weinberg, F., Hamanaka, R., Wheaton, W. W., Weinberg, S., Joseph, J., Lopez, M., Kalyanaraman, B., Mutlu, G. M., Budinger, G. R. and Chandel, N. S. 2010. Mitochondrial metabolism and ROS generation are essential for Kras-mediated tumorigenicity. Proc. Natl. Acad. Sci. USA 107, 8788-8793. https://doi.org/10.1073/pnas.1003428107
  27. Wong, N. A., Rae, F., Simpson, K. J., Murray, G. D. and Harrison, D. J. 2000. Genetic polymorphisms of cytochrome p4502E1 and susceptibility to alcoholic liver disease and hepatocellular carcinoma in a white population: a study and literature review, including meta-analysis. Mol. Pathol. 53, 88-93. https://doi.org/10.1136/mp.53.2.88
  28. Yi, S. J. and Jhun, B. H. 2004. Ethanol impairs insulin's actions through phosphatidylinositol 3-kinase. J. Med. Food 7, 24-30. https://doi.org/10.1089/109662004322984662
  29. Yokoyama, Y., Nagino, M. and Nimura, Y. 2007. Mechanism of impaired hepatic regeneration in cholestatic liver. J. Hepatobiliary Pancreat. Surg. 14, 159-166. https://doi.org/10.1007/s00534-006-1125-1
  30. Zhang, B. H., Ho, V. and Farrell, G. C. 2001. Specific involvement of G (alphai2) with epidermal growth factor receptor signaling in rat hepatocytes, and the inhibitory effect of chronic ethanol. Biochem. Pharmacol. 61, 1021-1027. https://doi.org/10.1016/S0006-2952(01)00554-8