Transfection of Smac/DIABLO sensitizes drug-resistant tumor cells to TRAIL or paclitaxel-induced apoptosis in vitro.
Smac/DIABLO is a recently identified protein released from mitochondria in response to apoptotic stimuli and promotes apoptosis by antagonizing inhibitor of apoptosis proteins (IAPs). In this study, we observed depressed Smac/DIABLO and increased XIAP expression in ovarian epithelial tissues ordered by normal, benign and malignant epithelia. In epithelial ovarian cancer (EOC), the expression of Smac/DIABLO decreased with the malignancy. Smac/DIABLO expression showed no correlation with TRAIL sensitivity, while lower Smac/DIABLO expression and decreased release of Smac/DIABLO from mitochondria upon apoptosis stimuli were observed in paclitaxel-resistant A2780/pac cells as compared to the sensitive controls. Ectopic Smac/DIABLO alone inhibited cell growth, arrested cells in G0/G1 phase, and sensitized drug-resistant EOC cells to TRAIL or paclitaxel-induced apoptosis. Increased apoptosis was associated with the down-regulation of XIAP, FLIP, and up-regulation of Smac/DIABLO, cytochrome c, p53, along with increased activity of caspase-3. Thus, over-expression of Smac/DIABLO is a promising strategy for drug-resistant ovarian cancer treatment.
Mao
Hong Luan
HL
Department of Obstetrics and Gynecology, QiLu Hospital of ShanDong University, Jinan, ShanDong 250012, China.
Liu
Pei Shu
PS
Zheng
Jing Fang
JF
Zhang
Pei Hai
PH
Zhou
Li Guang
LG
Xin
Gang
G
Liu
Chunxi
C
D000328:Adult; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D024101:Mitochondrial Proteins / Q000235:genetics* / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism; D010053:Ovary / Q000378:metabolism; D017239:Paclitaxel / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology; D014162:Transfection; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000235:genetics / Q000378:metabolism
D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C412403:DIABLO protein, human; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; D012333:RNA, Messenger; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D017239:Paclitaxel