First name
Aishwarya
Last name
Subramanian
Year of Study
Research Center
Thesis Title
Mitochondrial MARCH5 ubiquitin ligase abrogates MCL1-dependent resistance to BH3 mimetics via activation of NOXA
Thesis 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 ubiquitination 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.
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 ubiquitination 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.
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