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

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

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.

Original languageEnglish
Article numbere135438
JournalJCI Insight
Volume6
Issue number15
DOIs
Publication statusPublished - 2021 Aug 9

All Science Journal Classification (ASJC) codes

  • Medicine(all)

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