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Biochem Biophys Res Commun. 2013 Jan 25;430(4):1283-8. doi: 10.1016/j.bbrc.2012.11.136. Epub 2012 Dec 19.

Acidosis blocks CCAAT/enhancer-binding protein homologous protein (CHOP)- and c-Jun-mediated induction of p53-upregulated mediator of apoptosis (PUMA) during amino acid starvation.

Author information

1
Department of Pharmacology, Case Western Reserve University School of Medicine, Case Comprehensive Cancer Center, and University Hospitals Case Medical Center, Cleveland, OH 44106, USA.

Abstract

Cancer cells must avoid succumbing to a variety of noxious conditions within their surroundings. Acidosis is one such prominent feature of the tumor microenvironment that surprisingly promotes tumor survival and progression. We recently reported that acidosis prevents apoptosis of starved or stressed lymphoma cells through regulation of several Bcl-2 family members (Ryder et al., JBC, 2012). Mechanistic studies in that work focused on the acid-mediated upregulation of anti-apoptotic Bcl-2 and Bcl-xL, while additionally showing inhibition of glutamine starvation-induced expression of pro-apoptotic PUMA by acidosis. Herein we report that amino acid (AA) starvation elevates PUMA, an effect that is blocked by extracellular acidity. Knockdown studies confirm that PUMA induction during AA starvation requires expression of both CHOP and c-Jun. Interestingly, acidosis strongly attenuates AA starvation-mediated c-Jun expression, which correlates with PUMA repression. As c-Jun exerts a tumor suppressive function in this and other contexts, its inhibition by acidosis has broader implications for survival of cancer cells in the acidic tumor milieu.

PMID:
23261451
PMCID:
PMC3601792
DOI:
10.1016/j.bbrc.2012.11.136
[Indexed for MEDLINE]
Free PMC Article

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