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 3

Leptin rescues gallbladder cancer cells from gemcitabine-induced cell apoptosis.

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Leptin rescues gallbladder cancer cells from gemcitabine-induced cell ap...
(A) The viability of leptin–treated GBC cells in response to gemcitabine (GEM). SNU-308 and RCB-1130 cells were treated with GEM alone or in combination treatment with leptin. Cell viability was assessed by the MTT assay (n = 3; ***P < 0.001, **P < 0.01, 2-tailed Student’s t test). (B) RCB-1130 cells were starved for 24 hours and then treated with 100 nM gemcitabine or a combination of gemcitabine and leptin (100 ng/mL) for 24 hours. Cell toxicity was measured by the LDH assay (n = 3; **P < 0.01, ***P < 0.001), 1-way ANOVA followed by Tukey’s multiple comparisons). (C) Leptin attenuates GEM-induced caspase-3 activation. Caspase-3 activity was detected in SNU-308 and RCB-1130 cells (n = 3; ***P < 0.001, 2-tailed Student’s t test). (D) SNU-308 and RCB-1130 cells were plated in 100 nM GEM or 100 nM GEM in combination with leptin and treated for 24 hours in microtiter plates. Cell apoptosis was analyzed by the TUNEL assay. Blue spots represent cell nuclei by DAPI staining, and green spots represent apoptotic bodies by TUNEL staining (n = 3, 1-way ANOVA followed by Tukey’s multiple comparisons). Scale bar: 100 μm.