The mitochondrial uncoupling protein-2 promotes chemoresistance in cancer cells.
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 NH(2)-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.
Derdak
Zoltan
Z
Division of Gastroenterology and Liver Research Center, Brown Medical School and Rhode Island Hospital, Providence, Rhode Island, USA.
Mark
Nicholas M
NM
Beldi
Guido
G
Robson
Simon C
SC
Wands
Jack R
JR
Baffy
György
G
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity; D017209:Apoptosis / Q000235:genetics; D002455:Cell Division / Q000235:genetics; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic; D006019:Glycolysis; D006801:Humans; D007473:Ion Channels / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D008928:Mitochondria / Q000187:drug effects; D024101:Mitochondrial Proteins / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D016133:Polymerase Chain Reaction; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors; D014183:Transplantation, Heterologous; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D014466:Ultraviolet Rays; D000071246:Uncoupling Protein 2
D000970:Antineoplastic Agents; D007473:Ion Channels; D024101:Mitochondrial Proteins; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; C000604389:UCP2 protein, human; C000604390:Ucp2 protein, mouse; D000071246:Uncoupling Protein 2