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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 p53 in the modulation of LC3 II protein expression by leptin(A) HepG2 cells were treated with leptin for the indicated time periods and p53 protein expression levels were determined by Western blot analysis as described previously. (B) HepG2 cells were transfected with siRNA targeting p53 or scrambled control siRNA for 48 h, followed by stimulation with leptin for additional 48 h. FoxO3A protein expression levels were determined by Western blot analysis as described previously. (C) and (D) HepG2 cells(C) MCF-7 cells (D) and HCT 116 cells(E) were transfected with siRNA targeting p53 or scrambled control siRNA. After 48 h incubation, cells were stimulated with leptin for 48 h. LC3 II protein expression levels were determined by Western blot analysis as described previously. Representative image from three independent experiments are shown.
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Figure 6: Role of p53 in the modulation of LC3 II protein expression by leptin(A) HepG2 cells were treated with leptin for the indicated time periods and p53 protein expression levels were determined by Western blot analysis as described previously. (B) HepG2 cells were transfected with siRNA targeting p53 or scrambled control siRNA for 48 h, followed by stimulation with leptin for additional 48 h. FoxO3A protein expression levels were determined by Western blot analysis as described previously. (C) and (D) HepG2 cells(C) MCF-7 cells (D) and HCT 116 cells(E) were transfected with siRNA targeting p53 or scrambled control siRNA. After 48 h incubation, cells were stimulated with leptin for 48 h. LC3 II protein expression levels were determined by Western blot analysis as described previously. Representative image from three independent experiments are shown.

Mentions: For further characterization of the upstream signaling molecules, we investigated the involvement of p53. As shown in Fig. 6A, leptin increased p53 protein expression in a time-dependent manner in HepG2 cells. In addition, leptin-induced FoxO3A expression was prevented by gene silencing of p53 (Fig. 6B), providing evidence that p53 could regulate FoxO3A expression in leptin-treated cells. Furthermore, gene silencing of p53 completely abrogated leptin-induced LC3II protein expression both in HepG2 (Fig. 6C), MCF-7 cells (Fig. 6D) and colon cancer HCT 116 cells (Fig. 6E), suggesting a critical role of p53 signaling in leptin-induced autophagy induction.


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 p53 in the modulation of LC3 II protein expression by leptin(A) HepG2 cells were treated with leptin for the indicated time periods and p53 protein expression levels were determined by Western blot analysis as described previously. (B) HepG2 cells were transfected with siRNA targeting p53 or scrambled control siRNA for 48 h, followed by stimulation with leptin for additional 48 h. FoxO3A protein expression levels were determined by Western blot analysis as described previously. (C) and (D) HepG2 cells(C) MCF-7 cells (D) and HCT 116 cells(E) were transfected with siRNA targeting p53 or scrambled control siRNA. After 48 h incubation, cells were stimulated with leptin for 48 h. LC3 II protein expression levels were determined by Western blot analysis as described previously. Representative image from three independent experiments are shown.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 6: Role of p53 in the modulation of LC3 II protein expression by leptin(A) HepG2 cells were treated with leptin for the indicated time periods and p53 protein expression levels were determined by Western blot analysis as described previously. (B) HepG2 cells were transfected with siRNA targeting p53 or scrambled control siRNA for 48 h, followed by stimulation with leptin for additional 48 h. FoxO3A protein expression levels were determined by Western blot analysis as described previously. (C) and (D) HepG2 cells(C) MCF-7 cells (D) and HCT 116 cells(E) were transfected with siRNA targeting p53 or scrambled control siRNA. After 48 h incubation, cells were stimulated with leptin for 48 h. LC3 II protein expression levels were determined by Western blot analysis as described previously. Representative image from three independent experiments are shown.
Mentions: For further characterization of the upstream signaling molecules, we investigated the involvement of p53. As shown in Fig. 6A, leptin increased p53 protein expression in a time-dependent manner in HepG2 cells. In addition, leptin-induced FoxO3A expression was prevented by gene silencing of p53 (Fig. 6B), providing evidence that p53 could regulate FoxO3A expression in leptin-treated cells. Furthermore, gene silencing of p53 completely abrogated leptin-induced LC3II protein expression both in HepG2 (Fig. 6C), MCF-7 cells (Fig. 6D) and colon cancer HCT 116 cells (Fig. 6E), suggesting a critical role of p53 signaling in leptin-induced autophagy induction.

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