Autophagy induction by leptin contributes to suppression of apoptosis in cancer cells and xenograft model: Involvement of p53/FoxO3A axis

Abstract

Leptin, a hormone mainly produced from adipose tissue, has been shown to induce proliferation of cancer cells. However, the molecular mechanisms underlying leptin-induced tumor progression have not been clearly elucidated. In the present study, we investigated the role of autophagy in leptin-induced cancer cell proliferation using human hepatoma (HepG2) and breast cancer cells (MCF-7), and tumor growth in a xenograft model. Herein, we showed that leptin treatment caused autophagy induction as assessed by increase in expression of autophagy-related genes, including beclin-1, Atg5 and LC3 II, further induction of autophagosome formation and autophagic flux. Interestingly, inhibition of autophagic process by treatment with inhibitors and LC3B gene silencing blocked leptin-induced increase in cell number and suppression of apoptosis, indicating a crucial role of autophagy in leptin-induced tumor progression. Moreover, gene silencing of p53 or FoxO3A prevented leptin-induced LC3 II protein expression, suggesting an involvement of p53/FoxO3A axis in leptin-induced autophagy activation. Leptin administration also accelerated tumor growth in BALB/c nude mice, which was found to be autophagy dependent. Taken together, our results demonstrate that leptin-induced tumor growth is mediated by autophagy induction and autophagic process would be a promising target to regulate development of cancer caused by leptin production.

Unravelling the role of fatty acid metabolism in cancer through the FOXO3-FOXM1 axis

“…In agreement, it has been shown that the anti-proliferative effects of APN in cancer cells occur through the AMPK-FOXO3 pathway Nepal and Park, 2013). APN promotes autophagy in macrophages by suppressing the AKT-mediated phosphorylation of FOXO3 , while leptin treatment activates the autophagic process via the p53-FOXO3 axis, playing a critical role in restricting tumour growth (Nepal et al, 2015). Moreover, leptin administration Table 1 List of human homologues and orthologues of lipid-metabolic genes identified as DAF-16 and/or TCER-1 targets through RNA-Seq by Amrit et al (2016) (Amrit et al, 2016) and their potential functions in lipid metabolism.…”

“…also increases FOXO3 expression and the expression of genes related with autophagy (Nepal et al, 2015). However, it has also been documented that leptin administration inactivates FOXO3 in muscle cells (Sainz et al, 2009).…”

The update on transcriptional regulation of autophagy in normal and pathologic cells: A novel therapeutic target

“…P53 operates within a broader regulatory network to define autophagic control [152][153][154][155][156][157]. When cells are subjected to oncogenic activation or genotoxic stress and P53 is activated, P53 is shown to induce autophagy [152,153].…”

Modulation of Cell Death and Survival by Adipokines in the Liver

“…In this report, leptin-induced autophagy activation also contributes to the suppression of apoptosis of cancer cells, indicating that autophagy activation would be one of the survival mechanisms in hepatic cancer cells. 35) In conjunction with the results from adiponectin, autophagy induction would be a promising target for the modulation of cancer cell survival by adipokines.…”