Dysfunctional apoptosome activation in ovarian cancer: implications for chemoresistance.
Alterations in the regulation of apoptosis may contribute to the pathogenesis of cancer and resistance of tumor cells to chemotherapy. In mammalian cells, nonreceptor-mediated apoptosis occurs predominantly via assembly of a cytochrome c-dependent apoptosome complex containing caspase-9 and apoptotic protease-activating factor-1 (Apaf-1). We show here that cytosolic extracts from human ovarian carcinoma cell lines and primary ovarian tumor samples are deficient in their ability to activate procaspase-9 in the presence of cytochrome c and dATP when compared with control extracts. SKOV3, a human ovarian carcinoma cell line with diminished apoptosome activity, was significantly more resistant to chemotherapy-induced apoptosis than cell lines with functional Apaf-1 activity. This dysfunctional apoptosome activity was not explained by reduced expression levels of caspase-9 or Apaf-1. Moreover, expression levels of known inhibitors of the apoptosome, including heat shock protein 70, heat shock protein 90, or X-linked inhibitor of apoptosis, did not correlate with functional activity of the apoptosome. SKOV3, an ovarian cancer cell line with dysfunctional apoptosome activity, retains the ability to form the Apaf-1 oligomer; however, there is a diminished amount of caspase-9 in the apoptosome. The reduction in the amount of caspase-9 in the apoptosome in the SKOV3 cell line was associated with diminished caspase-3 activity. Dysfunctional apoptosome activation may contribute both to the pathogenesis of ovarian carcinoma and to chemoresistance.
Liu
J Rebecca
JR
Department of Obstetrics and Gynecology, University of Michigan Medical School, L4000 Women's Hospital, 1500 East Medical Center Drive, Ann Arbor, MI 48109, USA. rliu@umich.edu
Opipari
Anthony W
AW
Tan
Lijun
L
Jiang
Yibin
Y
Zhang
Yujing
Y
Tang
Huaijing
H
Nuñez
Gabriel
G
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000502:physiology*; D053477:Apoptotic Protease-Activating Factor 1; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D002945:Cisplatin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006801:Humans; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology*; D014176:Protein Biosynthesis; D011506:Proteins / Q000378:metabolism; D014407:Tumor Cells, Cultured; D051636:X-Linked Inhibitor of Apoptosis Protein
C506592:APAF1 protein, human; D000970:Antineoplastic Agents; D053477:Apoptotic Protease-Activating Factor 1; D011506:Proteins; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; C506433:CASP9 protein, human; D053453:Caspase 9; D020169:Caspases; D002945:Cisplatin