Uncoupling protein 2 mediates resistance to gemcitabine-induced apoptosis in hepatocellular carcinoma cell lines

被引:21
作者
Yu, Guangsheng [1 ,2 ]
Liu, Jun [1 ]
Xu, Kesen [2 ]
Dong, Jiahong [2 ,3 ]
机构
[1] Shandong Univ, Shandong Prov Hosp, Dept Hepatobiliary Surg, Jinan 250021, Peoples R China
[2] Shandong Univ, Qilu Hosp, Dept Hepatobiliary Surg, Jinan 250012, Peoples R China
[3] Chinese Gen PLA Hosp, Dept Hepatobiliary Surg, Beijing 100853, Peoples R China
基金
中国国家自然科学基金;
关键词
chemoresistance; hepatocellular carcinoma (HCC); uncoupling protein 2 (UCP2); gemcitabine; P53; INDUCTION; OBESITY; UCP2;
D O I
10.1042/BSR20150116
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
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页数:7
相关论文
共 31 条
[1]   Mitochondrial recoupling: a novel therapeutic strategy for cancer? [J].
Baffy, G. ;
Derdak, Z. ;
Robson, S. C. .
BRITISH JOURNAL OF CANCER, 2011, 105 (04) :469-474
[2]   Activation of P53 in HepG2 cells as surrogate to detect mutagens and promutagens in vitro [J].
Boehme, Kathleen ;
Dietz, Yasmin ;
Hewitt, Philip ;
Mueller, Stefan O. .
TOXICOLOGY LETTERS, 2010, 198 (02) :272-281
[3]   PYRUVATE OXIDATION IN RAT AND HUMAN SKELETAL-MUSCLE MITOCHONDRIA [J].
BOOKELMAN, H ;
TRIJBELS, JMF ;
SENGERS, RCA ;
JANSSEN, AJM ;
VEERKAMP, JH ;
STADHOUDERS, AM .
BIOCHEMICAL MEDICINE, 1978, 20 (03) :395-403
[4]   Uncoupling protein-3: A new member of the mitochondrial carrier family with tissue-specific expression [J].
Boss, O ;
Samec, S ;
PaoloniGiacobino, A ;
Rossier, C ;
Dulloo, A ;
Seydoux, J ;
Muzzin, P ;
Giacobino, JP .
FEBS LETTERS, 1997, 408 (01) :39-42
[5]   Transformed but not normal hepatocytes express UCP2 [J].
Carretero, MV ;
Torres, L ;
Latasa, U ;
García-Trevijano, ER ;
Prieto, J ;
Mato, JM ;
Avila, MA .
FEBS LETTERS, 1998, 439 (1-2) :55-58
[6]   α-Bisabolol induces dose- and time-dependent apoptosis in HepG2 cells via a Fas- and mitochondrial-related pathway, involves p53 and NFκB [J].
Chen, Wei ;
Hou, Jie ;
Yin, Yan ;
Jang, Jongchol ;
Zheng, Zhongliang ;
Fan, Handong ;
Zou, Guolin .
BIOCHEMICAL PHARMACOLOGY, 2010, 80 (02) :247-254
[7]   The mitochondrial uncoupling protein-2 promotes chemoresistance in cancer cells [J].
Derdak, Zoltan ;
Mark, Nicholas M. ;
Beldi, Guido ;
Robson, Simon C. ;
Wands, Jack R. ;
Baffy, Gyoergy .
CANCER RESEARCH, 2008, 68 (08) :2813-2819
[8]   UCP2, a mitochondrial protein regulated at multiple levels [J].
Donadelli, Massimo ;
Dando, Ilaria ;
Fiorini, Claudia ;
Palmieri, Marta .
CELLULAR AND MOLECULAR LIFE SCIENCES, 2014, 71 (07) :1171-1190
[9]   Uncoupling protein-2: A novel gene linked to obesity and hyperinsulinemia [J].
Fleury, C ;
Neverova, M ;
Collins, S ;
Raimbault, S ;
Champigny, O ;
LeviMeyrueis, C ;
Bouillaud, F ;
Seldin, MF ;
Surwit, RS ;
Ricquier, D ;
Warden, CH .
NATURE GENETICS, 1997, 15 (03) :269-272
[10]   How do uncoupling proteins uncouple? [J].
Garlid, KD ;
Jaburek, M ;
Jezek, P ;
Varecha, M .
BIOCHIMICA ET BIOPHYSICA ACTA-BIOENERGETICS, 2000, 1459 (2-3) :383-389