title: 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.
authors.affiliation: College of Pharmacy, Yeungnam University, Gyeongsangbuk-do, Republic of Korea.
authors.forename: Saroj
authors.initials: S
authors.lastname: Nepal
authors.affiliation: College of Pharmacy, Yeungnam University, Gyeongsangbuk-do, Republic of Korea.
authors.forename: Mi Jin
authors.initials: MJ
authors.lastname: Kim
authors.affiliation: College of Pharmacy and Medical Research Center, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea.
authors.forename: Jin Tae
authors.initials: JT
authors.lastname: Hong
authors.affiliation: Department of Pharmacology, School of Medicine, Kyungpook National University, Daegu, Republic of Korea.
authors.forename: Sang Hyun
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Institute of Pharmaceutical Research and Development, College of Pharmacy, Wonkwang University, Iksan, Jeonbuk, Republic of Korea.
authors.forename: Dong-Hwan
authors.initials: DH
authors.lastname: Sohn
authors.affiliation: Institute of Pharmaceutical Research and Development, College of Pharmacy, Wonkwang University, Iksan, Jeonbuk, Republic of Korea.
authors.forename: Sung Hee
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Institute of Pharmaceutical Research and Development, College of Pharmacy, Wonkwang University, Iksan, Jeonbuk, Republic of Korea.
authors.forename: Kyung
authors.initials: K
authors.lastname: Song
authors.affiliation: College of Pharmacy, Yeungnam University, Gyeongsangbuk-do, Republic of Korea.
authors.forename: Dong Young
authors.initials: DY
authors.lastname: Choi
authors.affiliation: College of Pharmacy, Yeungnam University, Gyeongsangbuk-do, Republic of Korea.
authors.forename: Eung Seok
authors.initials: ES
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Yeungnam University, Gyeongsangbuk-do, Republic of Korea.
authors.forename: Pil-Hoon
authors.initials: PH
authors.lastname: Park
mesh_terms: D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy / Q000235:genetics*; D000071187:Autophagy-Related Protein 5; D000071186:Beclin-1; D018450:Disease Progression; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D020868:Gene Silencing; D016158:Genes, p53; D056945:Hep G2 Cells; D006801:Humans; D020738:Leptin / Q000378:metabolism*; D061986:MCF-7 Cells; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000473:pathology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: C502778:ATG5 protein, human; D051017:Apoptosis Regulatory Proteins; D000071187:Autophagy-Related Protein 5; C494826:BAX protein, human; C491997:BECN1 protein, human; D000071186:Beclin-1; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D020738:Leptin; C477012:MAP1LC3A protein, human; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein
keywords: FoxO3A; apoptosis; autophagy; leptin; p53