Inhibition of MARCH5 ubiquitin ligase abrogates MCL1-dependent resistance to BH3 mimetics via NOXA.

Oncotarget
Aishwarya SubramanianMark Wade

Abstract

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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Citations

May 31, 2020·International Journal of Molecular Sciences·Isshin ShiibaShigeru Yanagi
Apr 21, 2017·Apoptosis : an International Journal on Programmed Cell Death·Rama RathoreDietrich Büsselberg
Feb 6, 2020·Cell Death and Differentiation·Manuel D HaschkaAndreas Villunger
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Jan 29, 2021·Cellular Signalling·Shujing LiHuijian Wu
Aug 3, 2021·International Journal of Biological Macromolecules·Pooja MittalIndrakant Kumar Singh

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Datasets Mentioned

BETA
ABT-737
ABT-199

Methods Mentioned

BETA
immunoprecipitation
transfection
Assay
PCR

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BCL-2 Family Proteins

BLC-2 family proteins are a group that share the same homologous BH domain. They play many different roles including pro-survival signals, mitochondria-mediated apoptosis and removal or damaged cells. They are often regulated by phosphorylation, affecting their catalytic activity. Here is the latest research on BCL-2 family proteins.