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Noxa mediates hepatic stellate cell apoptosis by proteasome inhibition
Author(s) -
Sosa Seda Ivette M.,
Mott Justin L.,
Akazawa Yuko,
Barreyro Fernando J.,
Bronk Steven F.,
Kaufmann Scott H.,
Gores Gregory J.
Publication year - 2010
Publication title -
hepatology research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.123
H-Index - 75
eISSN - 1872-034X
pISSN - 1386-6346
DOI - 10.1111/j.1872-034x.2010.00668.x
Subject(s) - hepatic stellate cell , apoptosis , proteasome , microbiology and biotechnology , programmed cell death , gene knockdown , proteasome inhibitor , biology , cell culture , inhibitor of apoptosis , cell , cell growth , cancer research , biochemistry , genetics , endocrinology
Aim: Induction of hepatic stellate cell (HSC) apoptosis is a viable therapeutic strategy to reduce liver fibrogenesis. Although BH3‐only proteins of the Bcl‐2 family trigger pro‐apoptotic pathways, the BH3‐only proteins mediating HSC apoptosis have not been well defined. Our aim, using proteasome inhibition as a model to induce HSC apoptosis, was to examine the BH3‐only proteins contributing to cell death of this key liver cell subtype. Methods: Apoptosis was induced by treating LX‐2 cells, an immortalized human hepatic stellate cell line, and primary rat stellate cells with the proteasome inhibitor MG‐132. Results: Treatment with proteasome inhibitors increased expression of Noxa both at the mRNA (16‐fold) and protein (22‐fold) levels indicating that both transcriptional and post‐translational mechanisms contributed to the increase in cellular Noxa levels. Knockdown of Noxa by siRNA significantly attenuated cell death, mechanistically implicating Noxa as a key apoptotic mediator of proteasome inhibitor‐induced cell death. Given the pivotal role for the anti‐apoptotic Bcl‐2 protein A1 in activated HSC survival, we determined if Noxa bound to this survival protein. Noxa was shown to physically bind the anti‐apoptotic Bcl‐2 protein A1 by co‐immunoprecipitation. Conclusions: Noxa contributes to proteasome inhibitor‐induced apoptosis of stellate cells likely by binding A1. Strategies to therapeutically increase Noxa expression may be useful for inducing HSC apoptosis.