Bile acid and cigarette smoke enhance the aggressive phenotype of esophageal adenocarcinoma cells by downregulation of the mitochondrial uncoupling protein-2
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Yuan Xu1, Paul L. Feingold1, Deborah R. Surman1, Kate Brown1, Sichuan Xi1, Jeremy L. Davis1, Jonathan Hernandez1, David S. Schrump1 and R. Taylor Ripley1
1Thoracic and GI Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20852, USA
R. Taylor Ripley, email: [email protected]
Keywords: bile acid; cigarette smoke; uncoupling protein-2; esophageal adenocarcinoma
Received: June 13, 2017 Accepted: October 25, 2017 Published: November 10, 2017
Limited information is available regarding mechanisms that link the known carcinogenic risk factors of gastro-esophageal reflux and cigarette smoking to metabolic alterations in esophageal adenocarcinoma (EAC). In the present study, we utilized a novel in-vitro model to examine whether bile acid and cigarette smoke increase the aggressiveness of EAC and whether these changes are associated with metabolic changes.
EAC cells (EACC) were exposed to 10 μg/ml cigarette smoke condensate (CSC) and/or 100 μM of the oncogenic bile acid, deoxycholic acid (DCA), for 5 days. These exposure conditions were chosen given their lack of effect on proliferation or viability. DCA and CSC increased invasion, migration, and clonogenicity in EAC cells. These changes were associated with concomitant increases in ATP, ROS, and lactate production indicative of increased mitochondrial respiration as well as glycolytic activity. DCA and CSC exposure significantly decreased expression of uncoupling protein-2 (UCP2), a mitochondrial inner membrane protein implicated in regulation of the proton gradient. Knockdown of UCP2 in EACC phenocopied DCA and CSC exposure as evidenced by increased cell migration, invasion, and clonogenicity, whereas over-expression of UCP2 had an inverse effect. Furthermore, over-expression of UCP2 abrogated DCA and CSC-mediated increases in lactate and ATP production in EACC.
DCA and CSC promote the aggressive phenotype of EACC with concomitant metabolic changes occurring via downregulation of UCP2. These results indicate that UCP2 is integral to the aggressive phenotype of EACC. This mechanism suggests that targeting alterations in cellular energetics may be a novel strategy for EAC therapy.
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