MFN2型
线粒体融合
品脱1
线粒体
癌症研究
粒体自噬
DNAJA3公司
胰腺癌
MFN1型
生物
氧化磷酸化
医学
癌症
线粒体DNA
细胞生物学
自噬
细胞凋亡
生物化学
遗传学
基因
作者
Meifang Yu,Nathalie Nguyen,Yanqing Huang,Daniel Lin,Tara N. Fujimoto,Jessica M. Molkentine,Amit Deorukhkar,Ya’an Kang,F. Anthony San Lucas,Conrad J. Fernandes,Eugene J. Koay,Sonal Gupta,Haoqiang Ying,Albert C. Koong,Joseph M. Herman,Jason B. Fleming,Anirban Maitra,Cullen M. Taniguchi
出处
期刊:JCI insight
[American Society for Clinical Investigation]
日期:2019-08-22
卷期号:4 (16)
被引量:104
标识
DOI:10.1172/jci.insight.126915
摘要
Pancreatic ductal adenocarcinoma (PDAC) requires mitochondrial oxidative phosphorylation (OXPHOS) to fuel its growth, however, broadly inhibiting this pathway might also disrupt essential mitochondrial functions in normal tissues. PDAC cells exhibit abnormally fragmented mitochondria that are essential to its oncogenicity, but it was unclear if this mitochondrial feature was a valid therapeutic target. Here, we present evidence that normalizing the fragmented mitochondria of pancreatic cancer via the process of mitochondrial fusion reduces OXPHOS, which correlates with suppressed tumor growth and improved survival in preclinical models. Mitochondrial fusion was achieved by genetic or pharmacologic inhibition of dynamin related protein-1 (Drp1) or through overexpression of mitofusin-2 (Mfn2). Notably, we found that oral leflunomide, an FDA-approved arthritis drug, promoted a two-fold increase in Mfn2 expression in tumors and was repurposed as a chemotherapeutic agent, improving the median survival of mice with spontaneous tumors by 50% compared to vehicle. We found that the chief tumor suppressive mechanism of mitochondrial fusion was enhanced mitophagy, which proportionally reduced mitochondrial mass and ATP production. These data suggest that mitochondrial fusion is a specific and druggable regulator of pancreatic cancer growth that could be rapidly translated to the clinic.
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