TY - JOUR
T1 - MCL1 participates in leptin-promoted mitochondrial fusion and contributes to drug resistance in gallbladder cancer
AU - Wang, Wei Jan
AU - Lai, Hong Yue
AU - Zhang, Fei
AU - Shen, Wan Jou
AU - Chu, Pei Yu
AU - Liang, Hsin Yin
AU - Liu, Ying Bin
AU - Wang, Ju Ming
N1 - Funding Information:
ADSCs were a gift from Chia-Ching Wu from the Department of Cell Biology and Anatomy at National Cheng Kung University. GBC cell lines, RCB-1130 and SNU-308, were gifts from Chien-Feng Li at the Department of Medical Research, Chi Mei Medical Center. This study was supported by CMU108-N-02 from China Medical University (to WJW) and MOST109-2320-B-006-026-MY3 and MOS110-2320-B-006-053 (to JMW) and MOST109-2320-B-039-003-MY2 to (WJW) from the Ministry of Science and Technology and, in part, by funding from the Headquarters of University Advancement at National Cheng Kung University, which is sponsored by the Ministry of Education.
Publisher Copyright:
Copyright: © 2021, Wang et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.
PY - 2021/8/9
Y1 - 2021/8/9
N2 - 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.
AB - 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.
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U2 - 10.1172/jci.insight.135438
DO - 10.1172/jci.insight.135438
M3 - Article
C2 - 34156978
AN - SCOPUS:85112728645
VL - 6
JO - JCI insight
JF - JCI insight
SN - 2379-3708
IS - 15
M1 - e135438
ER -