Regulation of HtrA2/Omi by X-linked inhibitor of apoptosis protein in chemoresistance in human ovarian cancer cells.
OBJECTIVE
Development of cisplatin resistance by cancer cells is a major hurdle in successful treatment of human ovarian cancer. However, the mechanism of cisplatin resistance in ovarian cancer cells remains unclear. In this study, we have examined the possible role of X-linked inhibitor of apoptosis protein (Xiap) in the development of cisplatin resistance in ovarian cancer cells and investigate if suppressed cytosolic high temperature required protein A (HtrA2/Omi) level is an important factor in cisplatin resistance in ovarian cancer.


METHODS
Cisplatin-sensitive (A2780 and COC1) and -resistant (A2780/DDP and COC1/DDP) ovarian cancer cells were cultured for different durations (0-24 h) and with different cisplatin concentrations (0-20 muM). Xiap content and cytosolic HtrA2/Omi content were analyzed by Western blot. Antisense oligonucleotides were used to downregulate Xiap content in ovarian cancer cells.


RESULTS
Cisplatin decreased Xiap content and increased cytosolic HtrA2/Omi content and caspase-3 activity in cisplatin-sensitive ovarian cancer cell lines (A2780 and COC1), but not in the resistant variants (A2780/DDP and COC1/DDP). Downregulation of Xiap by antisense Xiap oligonucleotides increased caspase-3 activity and sensitized cisplatin-resistant cells to cisplatin treatment. Cytosolic HtrA2/Omi level increased while Xiap was downregulated in cisplatin-resistant ovarian cancer cells.


CONCLUSIONS
Development of cisplatin resistance may be due to Xiap neutralizing caspase-3 activation and lower cytosolic HtrA2/Omi level in response to cisplatin in human ovarian cancer cells. Cytosolic HtrA2/Omi level is partly regulated by Xiap in ovarian cancer cells.
Yang
Xiaokui
X
Reproductive Biology Unit, Division of Gynaecologic Oncology, Department of Obstetrics and Gynaecology, University of Ottawa, Ottawa Health Research Institute, The Ottawa Hospital (Civic Campus), Ottawa, Ontario, Canada K1Y 4E9.
Xing
Hui
H
Gao
Qinglei
Q
Chen
Gang
G
Lu
Yunping
Y
Wang
Shixuan
S
Ma
Ding
D
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D000074923:High-Temperature Requirement A Serine Peptidase 2; D006801:Humans; D024101:Mitochondrial Proteins; D016376:Oligonucleotides, Antisense / Q000235:genetics; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000378:metabolism*; D014162:Transfection; D051636:X-Linked Inhibitor of Apoptosis Protein
D000970:Antineoplastic Agents; D024101:Mitochondrial Proteins; D016376:Oligonucleotides, Antisense; D011506:Proteins; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D012697:Serine Endopeptidases; C000615914:HTRA2 protein, human; D000074923:High-Temperature Requirement A Serine Peptidase 2; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D002945:Cisplatin