title: Inhibition of MARCH5 ubiquitin ligase abrogates MCL1-dependent resistance to BH3 mimetics via NOXA.
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.
authors.affiliation: Center for Genomic Science of IIT@SEMM, Fondazione Istituto Italiano di Tecnologia, Milano, Italy.
authors.forename: Aishwarya
authors.initials: A
authors.lastname: Subramanian
authors.affiliation: Center for Genomic Science of IIT@SEMM, Fondazione Istituto Italiano di Tecnologia, Milano, Italy.
authors.forename: Adrian
authors.initials: A
authors.lastname: Andronache
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA, USA.
authors.forename: Yao-Cheng
authors.initials: YC
authors.lastname: Li
authors.affiliation: Center for Genomic Science of IIT@SEMM, Fondazione Istituto Italiano di Tecnologia, Milano, Italy.
authors.forename: Mark
authors.initials: M
authors.lastname: Wade
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000494:pharmacology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D006801:Humans; D008565:Membrane Proteins / Q000187:drug effects / Q000378:metabolism*; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000187:drug effects / Q000378:metabolism*; D009596:Nitrophenols / Q000494:pharmacology; D010446:Peptide Fragments; D010879:Piperazines / Q000494:pharmacology; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000187:drug effects / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology; D044767:Ubiquitin-Protein Ligases / Q000187:drug effects / Q000378:metabolism*
chemical_list: C501332:ABT-737; D000814:Aniline Compounds; D000970:Antineoplastic Agents; C474007:Bax protein (53-86); D001713:Biphenyl Compounds; C579095:MCL1 protein, human; D008565:Membrane Proteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009596:Nitrophenols; C498702:PMAIP1 protein, human; D010446:Peptide Fragments; D010879:Piperazines; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; C515578:MARCHF5 protein, human; D044767:Ubiquitin-Protein Ligases; C528561:navitoclax
keywords: MARCH5; MCL1; NOXA; mitochondria; ubiquitin