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
• Journal: JCI insight (JCI Insight) Vol. 6 Issue 15 (08 09 2021) ISSN: 2379-3708 [Electronic] United States
• PMID: 34156978 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antimetabolites, Antineoplastic
• Apoptosis Regulatory Proteins
• Cebpd protein, mouse
• Leptin
• Mcl1 protein, mouse
• Myeloid Cell Leukemia Sequence 1 Protein
• STAT3 Transcription Factor
• Stat3 protein, mouse
• Deoxycytidine
• CCAAT-Enhancer-Binding Protein-delta
• Gemcitabine

Topics

• Adipocytes (metabolism)
• Animals
• Antimetabolites, Antineoplastic (pharmacology)
• Apoptosis Regulatory Proteins (metabolism)
• CCAAT-Enhancer-Binding Protein-delta (metabolism)
• Deoxycytidine (analogs & derivatives, pharmacology)
• Drug Discovery
• Drug Resistance, Neoplasm
• Gallbladder Neoplasms (drug therapy, metabolism)
• Leptin (metabolism)
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Mitochondrial Dynamics (drug effects, physiology)
• Myeloid Cell Leukemia Sequence 1 Protein (metabolism)
• STAT3 Transcription Factor (metabolism)
• Gemcitabine