Abstract
Oxidative stress induction is a common effector pathway for commonly used chemotherapeutic agents like gemcitabine (GEM) in hepatocellular carcinoma (HCC) patients. However, GEM alone or in combination with oxiplatin hardly renders any survival benefits to HCC patients. Mitochondrial uncoupling protein 2 (UCP2) is known to suppress mitochondrial reactive oxygen species (ROS) generation, thus mitigating oxidative stress-induced apoptosis. We demonstrate in the present study, using a panel of HCC cell lines that sensitivity to GEM in HCC well correlate with the endogenous level of UCP2 protein expression. Moreover, ectopic overexpression of UCP2 in a HCC cell line with low endogenous UCP2 expression, HLE, significantly decreased mitochondrial superoxide induction by the anti-cancer drug GEM. Conversely, UCP2 mRNA silencing by RNA interference in HCC cell lines with high endogenous UCP2 expression significantly enhanced GEM-induced mitochondrial superoxide generation and apoptosis. Cumulatively, our results suggest a critical role for mitochondrial uncoupling in GEM resistance in HCC cell lines. Hence, synergistic targeting of UCP2 in combination with other chemotherapeutic agents might be more potent in HCC patients.
Highlights
The uncoupling protein (UCP) family is a sub-category of mitochondrial anion-carrier proteins super-family and can be found in both animal and plant species [1]
In the present study, using cellular models of hepatocellular carcinoma (HCC) cell lines clinically treated with GEM, we investigated the involvement of uncoupling protein 2 (UCP2) expression in rendering cellular resistance to GEM and the anti-tumoral effect of GEM treatment associated to UCP2 inhibition
Differential steady state protein expression of UCP2 dictates sensitivity to gemcitabine To examine the roles UCP2 played in HCC cells, we first checked the endogenous UCP2 expression in a panel of four different HCC cell lines, HuH6, Hep3B, HepG2 and HLE
Summary
The uncoupling protein (UCP) family is a sub-category of mitochondrial anion-carrier proteins super-family and can be found in both animal and plant species [1]. Genome of mammalian species encode five UCP homologues (UCP1–5), with UCP1–3 demonstrating high sequence similarity [1,2,3]. G. Yu and others novel therapeutic target in different solid cancers. Using GEM rarely results in survival benefits to a patient with HCC, highlighting the need for identification of novel targets that dictate response to chemotherapy, the regulation of which in turn may improve sensitivity to GEM. Two evidences suggest that UCP2 targeting might be a potential therapeutic strategy for HCC, (a) UCP2 overexpressing colon cancer cells are more resistant to CPT-11, ((4S)-4,11-diethyl-3,4,12,14-tetrahydro-4-hydroxy3,14-dioxo-1H-pyrano[3 ,4 :6,7]indolizino[1,2-b]quinolin-9-yl [1,4 -bipiperidine]-1 -carboxylic acid ester hydrochloride), a topoisomerase I inhibitor and (b) genipin, a specific UCP2 inhibitor, enhanced sensitization to anthracyclin to drug-resistant leukaemia cells [16,17]. In the present study, using cellular models of HCC cell lines clinically treated with GEM, we investigated the involvement of UCP2 expression in rendering cellular resistance to GEM and the anti-tumoral effect of GEM treatment associated to UCP2 inhibition
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