Regulatory Role of Autophagy in Globular Adiponectin-Induced Apoptosis in Cancer Cells

  • Received : 2014.02.20
  • Accepted : 2014.05.02
  • Published : 2014.09.30


Adiponectin, an adipokine predominantly secreted from adipose tissue, exhibits diverse biological responses, including metabolism of glucose and lipid, and apoptosis in cancer cells. Recently, adiponectin has been shown to modulate autophagy as well. While emerging evidence has demonstrated that autophagy plays a role in the modulation of proliferation and apoptosis of cancer cells, the role of autophagy in apoptosis of cancer cell caused by adiponectin has not been explored. In the present study, we demonstrated that globular adiponectin (gAcrp) induces both apoptosis and autophagy in human hepatoma cell line (HepG2 cells) and breast cancer cells (MCF-7), as evidenced by increase in caspase-3 activity, Bax, microtubule-associated protein light chain 3-II (LC3 II) protein levels, and autophagosome formation. Interestingly, gene silencing of LC3B, an autophagy marker, significantly enhanced gAcrp-induced apoptosis in both HepG2 and MCF-7 cell lines, whereas induction of autophagy by rapamycin, an mTOR inhibitor, significantly prevented gAcrp-induced apoptosis in hepatoma cells HepG2. Furthermore, modulation of autophagy produced similar effects on gAcrp-induced Bax expression in HepG2 cells. These results implicate that induction of autophagy plays a regulatory role in adiponectin-induced apoptosis of cancer cells, and thus inhibition of autophagy would be a novel promising target to enhance the efficiency of cancer cell apoptosis by adiponectin.


Supported by : Yeungnam University


  1. Akifusa, S., Kamio, N., Shimazaki, Y., Yamaguchi, N., Nishihara, T. and Yamashita, Y. (2009) Globular adiponectin-induced RAW 264 apoptosis is regulated by a reactive oxygen species-dependent pathway involving Bcl-2. Free Radic. Biol. Med. 46, 1308-1316.
  2. Amaravadi, R. K. and Thompson, C. B. (2007) The roles of therapyinduced autophagy and necrosis in cancer treatment. Clin. Cancer Res. 13, 7271-7279.
  3. Cheng, T. J., Wang, Y. J., Kao, W. W., Chen, R. J. and Ho, Y. S. (2007) Protection against arsenic trioxide-induced autophagic cell death in U118 human glioma cells by use of lipoic acid. Food Chem. Toxicol. 45, 1027-1038.
  4. Essick, E. E., Wilson, R. M., Pimentel, D. R., Shimano, M., Baid, S., Ouchi, N. and Sam, F. (2013) Adiponectin modulates oxidative stress-induced autophagy in cardiomyocytes. PloS one 8, e68697.
  5. Gordy, C. and He, Y. W. (2012) The crosstalk between autophagy and apoptosis: where does this lead? Protein Cell 3, 17-27.
  6. Guo, R., Zhang, Y., Turdi, S. and Ren, J. (2013) Adiponectin knockout accentuates high fat diet-induced obesity and cardiac dysfunction: role of autophagy. Biochim. Biophys. Acta 1832, 1136-1148.
  7. Habeeb, B. S., Kitayama, J. and Nagawa, H. (2011) Adiponectin supports cell survival in glucose deprivation through enhancement of autophagic response in colorectal cancer cells. Cancer Sci. 102, 999-1006.
  8. Hamacher-Brady, A., Brady, N. R. and Gottlieb, R. A. (2006) Enhancing macroautophagy protects against ischemia/reperfusion injury in cardiac myocytes. J. Biol. Chem. 281, 29776-29787.
  9. Herman-Antosiewicz, A., Johnson, D. E. and Singh, S. V. (2006) Sulforaphane causes autophagy to inhibit release of cytochrome C and apoptosis in human prostate cancer cells. Cancer Res. 66, 5828-5835.
  10. Kelesidis, I., Kelesidis, T. and Mantzoros, C. S. (2006) Adiponectin and cancer: a systematic review. Br. J. Cancer 94, 1221-1225.
  11. Kroemer, G. and Levine, B. (2008) Autophagic cell death: the story of a misnomer. Nat. Rev. Mol. Cell Biol. 9, 1004-1010.
  12. Liang, Y., Yan, C. and Schor, N. F. (2001) Apoptosis in the absence of caspase 3. Oncogene 20, 6570-6578.
  13. Mathew, R., Karantza-Wadsworth, V. and White, E. (2007) Role of autophagy in cancer. Nat. Rev. Cancer 7, 961-967.
  14. Nepal, S., Kim, M. J., Lee, E. S., Kim, J. A., Choi, D. Y., Sohn, D. H., Lee, S. H., Song, K., Kim, S. H., Jeong, G. S., Jeong, T. C. and Park, P. H. (2014) Modulation of Atg5 expression by globular adiponectin contributes to autophagy flux and suppression of ethanolinduced cell death in liver cells. Food Chem. Toxicol. 68, 11-22.
  15. Nepal, S. and Park, P. H. (2013) Activation of autophagy by globular adiponectin attenuates ethanol-induced apoptosis in HepG2 cells: Involvement of AMPK/FoxO3A axis. Biochim. Biophys. Acta 1833, 2111-2125.
  16. Saxena, N. K., Fu, P. P., Nagalingam, A., Wang, J., Handy, J., Cohen, C., Tighiouart, M., Sharma, D. and Anania, F. A. (2010) Adiponectin modulates C-jun N-terminal kinase and mammalian target of rapamycin and inhibits hepatocellular carcinoma. Gastroenterology 139, 1762-1773, 1773 e1-5.
  17. Shin, S. W., Kim, S. Y. and Park, J. W. (2012) Autophagy inhibition enhances ursolic acid-induced apoptosis in PC3 cells. Biochim. Biophys. Acta 1823, 451-457.
  18. White, E. and DiPaola, R. S. (2009) The double-edged sword of autophagy modulation in cancer. Clin. Cancer Res. 15, 5308-5316.
  19. Yang, Z. J., Chee, C. E., Huang, S. and Sinicrope, F. (2011) Autophagy modulation for cancer therapy. Cancer Biol. Ther. 11, 169-176.

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