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

Nepal S, Kim MJ, Hong JT, Kim SH, Sohn DH, Lee SH, Song K, Choi DY, Lee ES, Park PH - Oncotarget (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: College of Pharmacy, Yeungnam University, Gyeongsangbuk-do, Republic of Korea.

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.

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Role of FoxO3A signaling in activation of autophagic process by leptin(A) HepG2 cells were incubated with leptin for the indicated time points. FoxO3A protein expression levels were determined by Western blot analysis as described previously. (B) and (C) HepG2 (B) and MCF-7 (C) cells were transfected with FoxO3A siRNA for 48 h, followed by incubation with indicated concentration of leptin for 48 h. LC3 II protein expression levels were determined by Western blot analysis.
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Figure 5: Role of FoxO3A signaling in activation of autophagic process by leptin(A) HepG2 cells were incubated with leptin for the indicated time points. FoxO3A protein expression levels were determined by Western blot analysis as described previously. (B) and (C) HepG2 (B) and MCF-7 (C) cells were transfected with FoxO3A siRNA for 48 h, followed by incubation with indicated concentration of leptin for 48 h. LC3 II protein expression levels were determined by Western blot analysis.

Mentions: We next further explored the potential signaling mechanisms involved in leptin-induced autophagy induction. For this, we first examined the effect of leptin on FoxO3A expression, since FoxO3A is closely associated with expression of genes related with autophagy [23]. As depicted in Fig. 5, leptin treatment increased FoxO3A protein expression in a time-dependent manner (Fig. 5A) and FoxO3A gene silencing inhibited leptin-induced LC3II protein expression both in HepG2 (Fig. 5B) and MCF-7 cells (Fig. 5C), suggesting that FoxO3A signaling is implicated in leptin-induced autophagy in cancer cells.


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

Nepal S, Kim MJ, Hong JT, Kim SH, Sohn DH, Lee SH, Song K, Choi DY, Lee ES, Park PH - Oncotarget (2015)

Role of FoxO3A signaling in activation of autophagic process by leptin(A) HepG2 cells were incubated with leptin for the indicated time points. FoxO3A protein expression levels were determined by Western blot analysis as described previously. (B) and (C) HepG2 (B) and MCF-7 (C) cells were transfected with FoxO3A siRNA for 48 h, followed by incubation with indicated concentration of leptin for 48 h. LC3 II protein expression levels were determined by Western blot analysis.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4466676&req=5

Figure 5: Role of FoxO3A signaling in activation of autophagic process by leptin(A) HepG2 cells were incubated with leptin for the indicated time points. FoxO3A protein expression levels were determined by Western blot analysis as described previously. (B) and (C) HepG2 (B) and MCF-7 (C) cells were transfected with FoxO3A siRNA for 48 h, followed by incubation with indicated concentration of leptin for 48 h. LC3 II protein expression levels were determined by Western blot analysis.
Mentions: We next further explored the potential signaling mechanisms involved in leptin-induced autophagy induction. For this, we first examined the effect of leptin on FoxO3A expression, since FoxO3A is closely associated with expression of genes related with autophagy [23]. As depicted in Fig. 5, leptin treatment increased FoxO3A protein expression in a time-dependent manner (Fig. 5A) and FoxO3A gene silencing inhibited leptin-induced LC3II protein expression both in HepG2 (Fig. 5B) and MCF-7 cells (Fig. 5C), suggesting that FoxO3A signaling is implicated in leptin-induced autophagy in cancer cells.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: College of Pharmacy, Yeungnam University, Gyeongsangbuk-do, Republic of Korea.

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.

Show MeSH
Related in: MedlinePlus