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The Mitochondrial Uncoupling Protein-2 Promotes Chemoresistance in Cancer Cells

¹ Division of Gastroenterology and Liver Research Center, Brown Medical School and Rhode Island Hospital, Providence, Rhode Island and ² Liver Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts

Requests for reprints: György Baffy, Brigham and Women's Hospital, Harvard Medical School and VA Boston Healthcare System, 150 South Huntington Avenue, Room A6-46, Boston, MA 02130. Phone: 857-364-4327; Fax: 857-364-4179; E-mail: gyorgy.baffy{at}va.gov.

Key Words: Uncoupling protein-2 • mitochondria • apoptosis • p53 • chemoresistance

Cancer cells acquire drug resistance as a result of selection pressure dictated by unfavorable microenvironments. This survival process is facilitated through efficient control of oxidative stress originating from mitochondria that typically initiates programmed cell death. We show this critical adaptive response in cancer cells to be linked to uncoupling protein-2 (UCP2), a mitochondrial suppressor of reactive oxygen species (ROS). UCP2 is present in drug-resistant lines of various cancer cells and in human colon cancer. Overexpression of UCP2 in HCT116 human colon cancer cells inhibits ROS accumulation and apoptosis after exposure to chemotherapeutic agents. Tumor xenografts of UCP2-overexpressing HCT116 cells retain growth in nude mice receiving chemotherapy. Augmented cancer cell survival is accompanied by altered NH₂-terminal phosphorylation of the pivotal tumor suppressor p53 and induction of the glycolytic phenotype (Warburg effect). These findings link UCP2 with molecular mechanisms of chemoresistance. Targeting UCP2 may be considered a novel treatment strategy for cancer. [Cancer Res 2008;68(8):2813–9]

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