Mitochondrial fusion exploits a therapeutic vulnerability of pancreatic cancer
Year: 2019
Type: article
Abstract: 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.
Source: JCI Insight
Authors: Meifang Yu, Nicholas D. 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
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $4,100
Funders: Robert and Janice McNair Foundation, V Foundation for Cancer Research, Cancer Prevention and Research Institute of Texas, Sidney Kimmel Foundation for Cancer Research, John S. Dunn Gulf Coast Consortium for Chemical Genomics, National Institutes of Health, University of Texas MD Anderson Cancer Center, National Cancer Institute, National Institute of Diabetes and Digestive and Kidney Diseases
Awards: G111615301, G1147702603, G1468253849, G1663282922, G1901027039, G2025267705, G2124445516, G2655961094, G274084553, G2978072047, G378605414, G4458821658, G4582187317, The Combinatorial Drug Discovery Program (CDDP), G5136865610, Recruitment of First-Time, Tenure-Track Faculty Members, G5465708471, G6736661663, G7197000807, G7837447426, G788993117, G8413015676, G8805934227, G9000013585, G9000240210, G9000316522, Cancer Center Support Grant, Baylor College of Medicine Cancer Center - Cancer Center Support Grant
OpenAlex ID: W2963642174