MCL1 participates in leptin-promoted mitochondrial fusion and contributes to drug resistance in gallbladder cancer
Wei-Jan Wang, Hong-Yue Lai, Fei Zhang, Wan-Jou Shen, Pei-Yu Chu, Hsin-Yin Liang, Ying-Bin Liu, Ju-Ming Wang
Wei-Jan Wang, Hong-Yue Lai, Fei Zhang, Wan-Jou Shen, Pei-Yu Chu, Hsin-Yin Liang, Ying-Bin Liu, Ju-Ming Wang
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Research Article Endocrinology Hepatology

MCL1 participates in leptin-promoted mitochondrial fusion and contributes to drug resistance in gallbladder cancer

Abstract

Obesity is a risk factor for gallbladder cancer (GBC) development, and it correlates with shorter overall survival. Leptin, derived from adipocytes, has been suggested to contribute to the growth of cancer cells; however, the detailed mechanism of leptin in GBC drug resistance remains uninvestigated. In this study, our finding that patients with GBC with a higher BMI were associated with increased GBC risks, including shortened survival, is clinically relevant. Moreover, obese NOD/SCID mice exhibited a higher circulating concentration of leptin, which is associated with GBC growth and attenuated gemcitabine efficacy. We further revealed that leptin can inhibit gemcitabine-induced GBC cell death through myeloid cell leukemia 1 (MCL1) activation. The transcription factor C/EBP δ (CEBPD) is responsive to activated STAT3 (pSTAT3) and contributes to MCL1 transcriptional activation upon leptin treatment. In addition, MCL1 mediates leptin-induced mitochondrial fusion and is associated with GBC cell survival. The findings in this study suggest the involvement of the pSTAT3/CEBPD/MCL1 axis in leptin-induced mitochondrial fusion and survival and provide a potentially new therapeutic target to improve the efficacy of gemcitabine in patients with GBC.

Authors

Wei-Jan Wang, Hong-Yue Lai, Fei Zhang, Wan-Jou Shen, Pei-Yu Chu, Hsin-Yin Liang, Ying-Bin Liu, Ju-Ming Wang

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Figure 4

STAT3 mediates leptin-induced gallbladder cancer cell survival through CEBPD activation.

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STAT3 mediates leptin-induced gallbladder cancer cell survival through C...
(A) Human adipocyte CM induces pSTAT3/CEBPD expression. RCB-1130 cells were exposed to adipocyte CM, and lysates were harvested according to the indicated time courses (n = 3). (B) pSTAT3/CEBPD expression following leptin treatment in GBC cells. SNU-308 and RCB-1130 cells were treated with leptin, and lysates were harvested according to the indicated time courses. Antibodies recognizing pSTAT3 (pY705), STAT3, CEBPD, and α-tubulin were used in Western blot analysis (n = 3). (C) STAT3 inhibitor (S3I-201) attenuated leptin-induced CEBPD mRNA and protein expression in GBC cells. Western blot analysis (n = 3) was conducted with lysates and qPCR assays (n = 3; **P < 0.01, 2-tailed Student’s t test) were conducted with total RNA harvested from SNU-308 and RCB-1130 cells. (D) Attenuation of CEBPD in RCB-1130 cells sensitizes them to gemcitabine (GEM) upon leptin treatment. Cells were pretreated with lentiviruses containing shLacZ (LacZ) or shCEBPD (CDKD). After 48 hours of incubation, experimental cells were treated with or without leptin and GEM. Death of experimental cells was examined by PI staining (n = 3; **P < 0.01, 2-tailed Student’s t test).