Prohibitin silencing reverses stabilization of mitochondrial integrity and chemoresistance in ovarian cancer cells by increasing their sensitivity to apoptosis.
Current approaches to the treatment of ovarian cancer are limited because of the development of resistance to chemotherapy. Prohibitin (Phb1) is a possible candidate protein that contributes to development of drug resistance, which could be targeted in neoplastic cells. Phb1 is a highly conserved protein that is associated with a block in the G0/G1 phase of the cell cycle and also with cell survival. Our study was designed to determine the role of Phb1 in regulating cellular growth and apoptosis in ovarian cancer cells. Our results showed that Phb1 content is differentially overexpressed in papillary serous ovarian carcinoma and endometrioid ovarian adenocarcinoma when compared to normal ovarian epithelium and was inversely related to Ki67 expression. Immunofluorescence microscopy and Western analyses revealed that Phb1 is primarily associated with the mitochondria in ovarian cancer cells. Over-expression of Phb1 by adenoviral Phb1 infection resulted in an increase in the percentage of ovarian cancer cells accumulating at G0/G1 phase of the cell cycle. Treatment of ovarian cancer cells with staurosporine (STS) induced apoptosis in a time-dependent manner. Phb1 over-expression induced cellular resistance to STS via the intrinsic apoptotic pathway. In contrast, silencing of Phb1 expression by adenoviral small interfering RNA (siRNA) sensitized ovarian cancer cells to STS-induce apoptosis. Taken together, these results suggest that Phb1 induces block at G0/G1 phase of the cell cycle and promotes survival of cancer cells. Furthermore, silencing of the Phb1 gene expression may prove to be a valuable therapeutic approach for chemoresistant ovarian cancer by increasing sensitivity of cancer cells to apoptosis.
Gregory-Bass
Rosalind C
RC
Department of Obstetrics and Gynecology, Cooperative Reproductive Research Center, Morehouse School of Medicine, Atlanta, GA 30310, USA.
Olatinwo
Moshood
M
Xu
Wei
W
Matthews
Roland
R
Stiles
Jonathan K
JK
Thomas
Kelwyn
K
Liu
Dong
D
Tsang
Benjamin
B
Thompson
Winston E
WE
D000256:Adenoviridae; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D015153:Blotting, Western; D018269:Carcinoma, Endometrioid / Q000188:drug therapy / Q000235:genetics*; D002291:Carcinoma, Papillary / Q000188:drug therapy / Q000235:genetics*; D053148:Caspase 3 / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D016193:G1 Phase; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D020868:Gene Silencing; D005822:Genetic Vectors; D006801:Humans; D019394:Ki-67 Antigen / Q000032:analysis; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics*; D010053:Ovary / Q000737:chemistry; D000091402:Prohibitins; D034741:RNA, Small Interfering / Q000378:metabolism; D011994:Recombinant Proteins; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D016192:Resting Phase, Cell Cycle; D019311:Staurosporine / Q000494:pharmacology; D015854:Up-Regulation
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D019394:Ki-67 Antigen; C000717328:PHB protein, human; D000091402:Prohibitins; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D012097:Repressor Proteins; D053148:Caspase 3; D019311:Staurosporine