title: 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.
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.
authors.affiliation: Department of Pharmacology, Case Western Reserve University School of Medicine, Case Comprehensive Cancer Center, and University Hospitals Case Medical Center, Cleveland, OH 44106, USA.
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Ryder
authors.forename: Karen
authors.initials: K
authors.lastname: McColl
authors.forename: Clark W
authors.initials: CW
authors.lastname: Distelhorst
mesh_terms: D000138:Acidosis / Q000378:metabolism*; D000596:Amino Acids / Q000172:deficiency*; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D045744:Cell Line, Tumor; D055785:Gene Knockdown Techniques; D008223:Lymphoma / Q000378:metabolism*; D051379:Mice; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D051742:Transcription Factor CHOP / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics
chemical_list: D000596:Amino Acids; D051017:Apoptosis Regulatory Proteins; C497250:Ddit3 protein, mouse; C488588:PUMA protein, mouse; D016755:Proto-Oncogene Proteins c-jun; D025521:Tumor Suppressor Proteins; D051742:Transcription Factor CHOP