Uncoupling protein-2 knockdown mediates the cytotoxic effects of cisplatin.
Cisplatin is among the most important chemotherapeutic agents ever developed. However, more than a generation after its clinical introduction, its exact mechanism of action on tumor cells is not fully defined. The aim of this study was to investigate the role of oxidative stress as a mediator of cisplatin action on colon cancer cells, studying the influence of mitochondrial physiology and composition on its effectiveness. The chemosensitivity shown by cancer cells to mechanistically dissimilar antitumor drugs is shown to be associated with their capacity to induce early alterations in mitochondrial and redox metabolism. Specifically, cisplatin exerted a marked pro-oxidative action on mitochondria by inhibiting resting respiration and stimulating the immediate generation of ROS in isolated mitochondria. Antioxidants and mitochondrial uncouplers counteracted cisplatin-induced cytotoxicity in tumor cells, reflecting that oxidative stress and the inhibition of mitochondrial uncoupling are relevant to its antiproliferative activity. Additionally, inhibition of uncoupling protein-2 (UCP2) caused cytotoxicity in colon cancer cells via ROS of mitochondrial origin. In conclusion, we show for the first time that UCP2 knockdown participates in the mechanism of action of cisplatin, thus providing evidence that targeting UCP2 may offer clinical benefit in the treatment of cancer.
Santandreu
Francisca M
FM
Grupo Multidisciplinar de Oncología Traslacional, Institut Universitari d'Investigació en Ciències de la Salut, Universitat de les Illes Balears, Palma de Mallorca 07122, Illes Balears, Spain.
Roca
Pilar
P
Oliver
Jordi
J
D000970:Antineoplastic Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D007473:Ion Channels / Q000378:metabolism*; D008928:Mitochondria / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism*; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D014407:Tumor Cells, Cultured; D000071246:Uncoupling Protein 2
D000970:Antineoplastic Agents; D000975:Antioxidants; D007473:Ion Channels; D024101:Mitochondrial Proteins; D017382:Reactive Oxygen Species; C000604389:UCP2 protein, human; D000071246:Uncoupling Protein 2; D006861:Hydrogen Peroxide; D002945:Cisplatin