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

Abstract

// Saroj Nepal 1 , Mi Jin Kim 1 , Jin Tae Hong 2 , Sang Hyun Kim 3 , Dong-Hwan Sohn 4 , Sung Hee Lee 4 , Kyung Song 4 , Dong Young Choi 1 , Eung Seok Lee 1 and Pil-Hoon Park 1 1 College of Pharmacy, Yeungnam University, Gyeongsangbuk-do, Republic of Korea 2 College of Pharmacy and Medical Research Center, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea 3 Department of Pharmacology, School of Medicine, Kyungpook National University, Daegu, Republic of Korea 4 Institute of Pharmaceutical Research and Development, College of Pharmacy, Wonkwang University, Iksan, Jeonbuk, Republic of Korea Correspondence: Pil-Hoon Park, email: // Keywords : apoptosis, autophagy, FoxO3A, leptin, p53 Received : October 25, 2014 Accepted : January 15, 2015 Published : January 31, 2015 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.