KSBB Journal

The Korean Society for Biotechnology and Bioengineering (한국생물공학회)
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Anti-cancer Effects of Luteolin and Its Novel Mechanism in HepG2 Hepatocarcinoma Cell

루테올린의 간암세포 성장 억제효능 및 새로운 작용기전

  • 황진택 (한국식품연구원 바이오제론 연구단) ;
  • 양혜정 (한국식품연구원 바이오제론 연구단)
  • Received : 2010.09.13
  • Accepted : 2010.12.03
  • Published : 2010.12.31
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Abstract

In this study, we investigated the ability of luteolin, a plant derived flavonoid on hepatocarcinoma cell growth using HepG2 cell culture system. We found that luteolin increased the Smac/DIABLO releases, a mitochondrial protein that potentiates apoptosis. Luteolin also induced either transcriptional activity or expression of PPAR-gamma, a target of cancer growth that PPAR-gamma agonist sensitizes to apoptosis in certain cancer types. To find the possible upstream target molecules of PPAR-gamma activated by luteolin treatment, we used compound C, a specific inhibitor of AMP-activated protein kinase. Pre-treatment of Compound C significantly restored the activation or expression of PPAR-gamma stimulated by luteolin. This result indicated that AMPK signaling might be involved in the activation or expression of PPAR-gamma signaling pathway stimulated by luteolin. Moreover, we also found that luteolin inhibited the insulin-stimulated Akt phosphorylation as well as AICAR, a specific AMPK activator. These results propose that luteolin significantly induces cancer cell death through modulating survival signal pathways such as PPAR-gamma and Akt. AMPK signaling pathway may be an upstream regulator for survival signal pathways such as PPAR-gamma and Akt stimulated by luteolin.

Keywords

References

  1. Nakagama, H. (2010) PPARgamma and cancer. Nippon Rinsho. 68: 323-9.
  2. Lyon, C. M., D. M. Klinge, K. C. Do, M. J. Grimes, C. L. Thomas, L. A. Damiani, T. H. March, C. A. Stidley, and S. A. Belinsky (2009) Rosiglitazone prevents the progression of preinvasive lung cancer in a murine model. Carcinogenesis 30: 2095-9. https://doi.org/10.1093/carcin/bgp260
  3. Yu, J., B. Shen, E. S. Chu, N. Teoh, K. F. Cheung, C. W. Wu, S. Wang, C. N. Lam, H. Feng, J. Zhao, A. S. Cheng, K. F. To, H. L. Chan, and J. J. Sung (2010) Inhibitory role of peroxisome proliferator-activated receptor gamma in hepatocarcinogenesis in mice and in vitro. Hepatology 51: 2008-19. https://doi.org/10.1002/hep.23550
  4. Carnero, A. (2010) The PKB/AKT pathway in cancer. Curr. Pharm. Des. 16: 34-44. https://doi.org/10.2174/138161210789941865
  5. Wysocki, P. J. (2010) Targeted therapy of hepatocellular cancer. Expert Opin. Investig. Drugs 19: 265-74. https://doi.org/10.1517/13543780903514110
  6. Luo, Z., M. Zang, and W. Guo (2010) AMPK as a metabolic tumor suppressor: control of metabolism and cell growth. Future Oncol. 6: 457-70. https://doi.org/10.2217/fon.09.174
  7. Hien, T. T., H. G. Kim, E. H. Han, K. W. Kang, and H. G. Jeong (2010) Molecular mechanism of suppression of MDR1 by puerarin from Pueraria lobata via NF-kappaB pathway and cAMP-responsive element transcriptional activity-dependent up-regulation of AMP-activated protein kinase in breast cancer MCF-7/adr cells. Mol. Nutr. Food Res. 54: 918-28. https://doi.org/10.1002/mnfr.200900146
  8. Guo, W., E. Kong, and M. Meydani (2009) Dietary polyphenols, inflammation, and cancer. Nutr. Cancer 61: 807-10. https://doi.org/10.1080/01635580903285098
  9. Tachibana, H. (2009) Molecular basis for cancer chemoprevention by green tea polyphenol EGCG. Forum Nutr. 61: 156-69.
  10. Lopez-Lazaro M. (2009) Distribution and biological activities of the flavonoid luteolin. Mini Rev. Med. Chem. 9: 31-59. https://doi.org/10.2174/138955709787001712
  11. Lee, H. J., C. J. Wang, H. S. Kuo, F. P. Chou, L. F. Jean, and T. H. Tseng (2005) Induction apoptosis of luteolin in human hepatoma HepG2 cells involving mitochondria translocation of Bax/Bak and activation of JNK. Toxicol. Appl. Pharmacol. 203: 124-131. https://doi.org/10.1016/j.taap.2004.08.004
  12. Gradzka, I. (2006) Mechanisms and regulation of the programmed cell death. Postepy Biochem. 52: 157-65.
  13. Nishizuka, M. and M. Imagawa (2010) PPARgamma target genes and the molecular mechanism of transcriptional control by PPARgamma. Nippon Rinsho. 68: 189-93.
  14. Patel, L., I. Pass, P. Coxon, C. P. Downes, S. A. Smith, and C. H. Macphee (2001) Tumor suppressor and anti-inflammatory actions of PPAR-gamma agonists are mediated via upregulation of PTEN. Curr. Biol. 11: 764-8. https://doi.org/10.1016/S0960-9822(01)00225-1
  15. Farrow, B. and B. M. Evers (2003) Activation of PPARgamma increases PTEN expression in pancreatic cancer cells. Biochem. Biophys. Res. Commun. 301: 50-3. https://doi.org/10.1016/S0006-291X(02)02983-2
  16. Chen, W. C., M. S. Lin, and X. Bai (2005) Induction of apoptosis in colorectal cancer cells by peroxisome proliferators-activated receptor gamma activation up-regulating PTEN and inhibiting PI3K activity. Chin. Med. J. (Engl) 118: 1477-81.
  17. Lee, S. Y., G. Y. Hur, K. H. Jung, H. C. Jung, S. Y. Lee, J. H. Kim, C. Shin, J. J. Shim, K. H. In, K. H. Kang, and S. H. Yoo (2006) PPAR-gamma agonist increase gefi tinib's antitumor activity through PTEN expression. Lung Cancer 51: 297-301. https://doi.org/10.1016/j.lungcan.2005.10.010
  18. Giovannini, C., B. Scazzocchio, R. Varì, C. Santangelo, M. D'Archivio, and R. Masella (2007) Apoptosis in cancer and atherosclerosis: polyphenol activities. Ann. Ist. Super Sanita. 43: 406-16.
  19. Huang, C. H., S. J. Tsai, Y. J. Wang, M. H. Pan, J. Y. Kao, and T. D. Way (2009) EGCG inhibits protein synthesis, lipogenesis, and cell cycle progression through activation of AMPK in p53 positive and negative human hepatoma cells. Mol. Nutr. Food Res. 53: 1156-65. https://doi.org/10.1002/mnfr.200800592
  20. Puissant, A., G. Robert, N. Fenouille, F. Luciano, J. P. Cassuto, S. Raynaud, and P. Auberger (2010) Resveratrol promotes autophagic cell death in chronic myelogenous leukemia cells via JNK-mediated p62/SQSTM1 expression and AMPK activation. Cancer Res. 70: 1042-52. https://doi.org/10.1158/0008-5472.CAN-09-3537
  21. Lea, M. A., M. Sura, and C. Desbordes (2004) Inhibition of cell proliferation by potential peroxisome proliferatoractivated receptor (PPAR) gamma agonists and antagonists. Anticancer Res. 24: 2765-71.
  22. Horbinski, C. and C. T. Chu (2005) Kinase signaling cascades in the mitochondrion: a matter of life or death. Free Radic. Biol. Med. 38: 2-11. https://doi.org/10.1016/j.freeradbiomed.2004.09.030
  23. Maddika, S., S. R. Ande, S. Panigrahi, T. Paranjothy, K. Weglarczyk, A. Zuse, M. Eshraghi, K. D. Manda, E. Wiechec, and M. Los (2007) Cell survival, cell death and cell cycle pathways are interconnected: implications for cancer therapy. Drug Resist. Updat. 10: 13-29. https://doi.org/10.1016/j.drup.2007.01.003
  24. Kim, K. Y., A. Baek, J. E. Hwang, Y. A. Choi, J. Jeong, M. S. Lee, D. H. Cho, J. S. Lim, K. I. Kim, and Y. Yang (2009) Adiponectin-activated AMPK stimulates dephosphorylation of AKT through protein phosphatase 2A activation. Cancer Res. 69: 4018-26.