MCL1 participates in leptin-promoted mitochondrial fusion and contributes to drug resistance in gallbladder cancer
Wei-Jan Wang, … , Ying-Bin Liu, Ju-Ming Wang
Wei-Jan Wang, … , Ying-Bin Liu, Ju-Ming Wang
Published June 22, 2021
Citation Information: JCI Insight. 2021;6(15):e135438. https://doi.org/10.1172/jci.insight.135438.
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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 1

Evaluation of the significance of obesity in gallbladder cancer.

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Evaluation of the significance of obesity in gallbladder cancer. (A–C) N...
(A–C) Numbers of patients at different clinical stages for those with BMI ≥24 (n = 30) and BMI <24 (n = 45). Numbers of metastases and nonmetastases for patients with BMI ≥24 and BMI <24. Numbers of instances of microvascular and nonmicrovascular invasion for patients with BMI ≥24 and BMI <24 (χ2 test). (D) Kaplan-Meier plots of the overall survival of patients with GBC based on BMI <24 (n = 45) or BMI ≥24 (n = 30) (Cox proportional regression analysis). (E) Four-week-old male NOD/SCID mice were fed with normal diet or high-fat diet for 12 weeks and then sacrificed at the age of 16 weeks. Body weights of normal diet– and high-fat diet–fed mice (n = 4; *P < 0.05) were recorded, and circulating leptin levels were measured by ELISA (n = 4; ***P < 0.0001, 2-tailed Student’s t test). (F) After being fed a normal or a high-fat diet for 12 weeks, mice were injected with GBC cells RCB-1130 (4 × 106/mice). Tumors were allowed to grow for 14 days, and tumor volume was measured twice per week for 4 weeks using a caliper. Tumor volume was calculated according to the formula (length × width2)/2. The mice were sacrificed at the end of the experiment, and the tumors were removed and weighed (n = 4; *P < 0.05, 2-tailed Student’s t test).