Critical role of autophagy induction in tumor growth and activation of cancer metabolism by leptin in breast cancer Cells


Year:

Session type:

Theme:

Nirmala Tilija Pun1,Duc-Vinh Pham1,Pawan Kumarraut1,Ananda Baral1,Su-min Lee1,Thi-Hong-Van Tran2,Pil-Hoon Park*1
1Yeungnam University,2Yeungnam Univesity

Abstract

Background

Leptin, a hormone predominantly produced by adipose tissue, induces tumor growth and cancer cell specific metabolism. However, its underlying mechanisms remain elusive. Recent studies have demonstrated that autophagy is implicated in various leptin-induced biological responses in cancer cells. In this study, we examined the role of autophagy in the activation of breast cancer cells metabolism and its underlying mechanisms.

Method

Role of autophagy in leptin-stimulated ATP production, mitochondrial oxidative phosphorylation, accumulation of lipid droplet, and free fatty acid production were examined in MCF-7 human breast cancer cells. Effect of leptin on SREBP-1 expression was examined by Western blot analysis. In addition, the role of SREBP-1 in the modulation of cancer cell metabolism was further explored by gene silencing. Observations from in vitro studies were further validated in MCF-7 xenograft in vivo model.

Results

Leptin treatment induced significant increase in ATP production in MCF-7 cells. Pretreatment with Oligomycin or Etomoxir, pharmacological inhibitor of mitochondrial ATP synthase and fatty acid transferase, respectively, suppressed leptin-induced ATP production, indicating that ATP production by leptin is mediated by mitochondrial oxidative phosphorylation. Pretreatment with an autophagy inhibitor or gene silencing of LC3B substantially suppressed leptin-stimulated ATP production. All the results from in vitro studies were also observed in MCF-7 xenograft model. Leptin also significantly increased SREBP-1 expression. Inhibition of autophagy suppressed leptin-stimulated SREBP-1 expression. Furthermore, gene silencing of SREBP-1 prominently suppressed leptin-stimulated ATP production in MCF-7 cells.

Conclusion

The results observed in this study suggest that autophagy critically contributes to leptin-induced cancer cell specific metabolism, which is mediated, at least in part, via SREBP-1 induction.