Inhibition of MARCH5 ubiquitin ligase abrogates MCL1-dependent resistance to BH3 mimetics via NOXA
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Aishwarya Subramanian1, Adrian Andronache1, Yao-Cheng Li2 and Mark Wade1
1 Center for Genomic Science of IIT@SEMM, Fondazione Istituto Italiano di Tecnologia, Milano, Italy
2 Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA, USA
Mark Wade, email:
Keywords: MARCH5, mitochondria, MCL1, NOXA, ubiquitin
Received: February 03, 2016 Accepted: February 09, 2016 Published: February 21, 2016
BH3 mimetic compounds induce tumor cell death through targeted inhibition of anti-apoptotic BCL2 proteins. Resistance to one such compound, ABT-737, is due to increased levels of anti-apoptotic MCL1. Using chemical and genetic approaches, we show that resistance to ABT-737 is abrogated by inhibition of the mitochondrial RING E3 ligase, MARCH5. Mechanistically, this is due to increased expression of pro-apoptotic BCL2 family member, NOXA, and is associated with MARCH5 regulation of MCL1 ubiquitylation and stability in a NOXA-dependent manner. MARCH5 expression contributed to an 8-gene signature that correlates with sensitivity to the preclinical BH3 mimetic, navitoclax. Furthermore, we observed a synthetic lethal interaction between MCL1 and MARCH5 in MCL1-dependent breast cancer cells. Our data uncover a novel level at which the BCL2 family is regulated; furthermore, they suggest targeting MARCH5-dependent signaling will be an effective strategy for treatment of BH3 mimetic-resistant tumors, even in the presence of high MCL1.
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