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.
MITOCHONDRIAL MARCH5 UBIQUITIN LIGASE ABROGATES MCL1-DEPENDENT RESISTANCE TO BH3 MIMETICS VIA STABILIZATION OF NOXA / A. Subramanian ; supervisor: M. Wade ; internal Advisor: S. POLO ; external Phd advisor:: D.ARNOULT,. UNIVERSITA' DEGLI STUDI DI MILANO, 2016 Mar 18. 27. ciclo, Anno Accademico 2015. [10.13130/subramanian-aishwarya_phd2016-03-18].
MITOCHONDRIAL MARCH5 UBIQUITIN LIGASE ABROGATES MCL1-DEPENDENT RESISTANCE TO BH3 MIMETICS VIA STABILIZATION OF NOXA
A. Subramanian
2016
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.File | Dimensione | Formato | |
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phd_unimi_R09854.pdf
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