Role of mitochondrial uncoupling protein 2 in cancer cell resistance to gemcitabine

• Published in: Biochimica et biophysica acta 2012-10, Vol.1823 (10), p.1856-1863
• Main Authors: Dalla Pozza, Elisa, Fiorini, Claudia, Dando, Ilaria, Menegazzi, Marta, Sgarbossa, Anna, Costanzo, Chiara, Palmieri, Marta, Donadelli, Massimo
• Format: Article
• Language: English
• Subjects: Acetylcysteine - pharmacology; Apoptosis; Apoptosis - drug effects; Cancer; Cell Line, Tumor; Cell Proliferation - drug effects; Deoxycytidine - analogs & derivatives; Deoxycytidine - pharmacology; Drug Resistance, Neoplasm - drug effects; Gemcitabine; Gene Expression Regulation, Neoplastic - drug effects; Humans; Ion Channels - antagonists & inhibitors; Ion Channels - genetics; Ion Channels - metabolism; Iridoids - pharmacology; Mitochondrial Proteins - antagonists & inhibitors; Mitochondrial Proteins - genetics; Mitochondrial Proteins - metabolism; Neoplasms - enzymology; Neoplasms - genetics; Neoplasms - metabolism; Neoplasms - pathology; Oxidative stress; Poly(ADP-ribose) Polymerases - metabolism; Resistance; RNA, Messenger - genetics; RNA, Messenger - metabolism; Superoxide Dismutase - metabolism; Superoxides - metabolism; Uncoupling Agents; Uncoupling Protein 2
• ISSN: 0167-4889; 0006-3002; 1879-2596
• DOI: 10.1016/j.bbamcr.2012.06.007

Cancer cells exhibit an endogenous constitutive oxidative stress higher than that of normal cells, which renders tumours vulnerable to further reactive oxygen species (ROS) production. Mitochondrial uncoupling protein 2 (UCP2) can mitigate oxidative stress by increasing the influx of protons into the mitochondrial matrix and reducing electron leakage and mitochondrial superoxide generation. Here, we demonstrate that chemical uncouplers or UCP2 over-expression strongly decrease mitochondrial superoxide induction by the anticancer drug gemcitabine (GEM) and protect cancer cells from GEM-induced apoptosis. Moreover, we show that GEM IC50 values well correlate with the endogenous level of UCP2 mRNA, suggesting a critical role for mitochondrial uncoupling in GEM resistance. Interestingly, GEM treatment stimulates UCP2 mRNA expression suggesting that mitochondrial uncoupling could have a role also in the acquired resistance to GEM. Conversely, UCP2 inhibition by genipin or UCP2 mRNA silencing strongly enhances GEM-induced mitochondrial superoxide generation and apoptosis, synergistically inhibiting cancer cell proliferation. These events are significantly reduced by the addition of the radical scavenger N-acetyl-l-cysteine or MnSOD over-expression, demonstrating a critical role of the oxidative stress. Normal primary fibroblasts are much less sensitive to GEM/genipin combination. Our results demonstrate for the first time that UCP2 has a role in cancer cell resistance to GEM supporting the development of an anti-cancer therapy based on UCP2 inhibition associated to GEM treatment. ► Mitochondrial uncoupling reduces GEM effect in cancer cells ► GEM and UCP2 inhibition synergistically inhibit cancer cell proliferation ► GEM and UCP2 inhibition induce ROS-mediated apoptosis in cancer cells ► UCP2 expression is a potential predictive biomarker of cancer resistance to GEM ► UCP2 is an efficient molecular target to selectively inhibit cancer cell proliferation