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Caspase-1 Is Down-regulated in Human Ovarian Cancer Cells and the Overexpression of Caspase-1 Induces Apoptosis

Departments of ¹ Obstetrics and Gynecology and ² Pathology, University of British Columbia, Vancouver, British Columbia, Canada

Requests for reprints: Nelly Auersperg, Department of Obstetrics and Gynaecology, University of British Columbia, B.C. Women's Hospital, Room 2H30, 4490 Oak Street, Vancouver, British Columbia, Canada V6H 3V5. Phone: 604-875-2424, ext. 6354; Fax: 604-875-2725; E-mail: auersper{at}interchange.ubc.ca.

Caspase-1 plays a key role in the processing of cytokines and in the apoptosis of neurons and macrophages. Whether it also causes apoptosis of cancer cells has been unclear. In this study, we screened an array of apoptosis-related proteins in ovarian carcinoma cell lines and their tissue of origin, ovarian surface epithelium (OSE). Caspase-1 protein was abundant in OSE and in nontumorigenic OSE with extended but limited life spans (immortalized OSE), but was reduced in the cancer lines A2780 and OVCAR10. By Western blot and immunofluorescence, caspase-1 levels were greatly reduced in six of eight ovarian carcinoma lines compared with OSE. By real-time reverse transcription-PCR, steady-state transcripts of the CASP1 gene were proportional to protein levels. Caspase-1 overexpression caused significant apoptosis, but overexpression of a caspase-1 mutant without catalytic activity did not, confirming that the effect was caspase-1–specific. Immunofluorescence of caspase-1 and terminal nucleotidyl transferase–mediated dUTP-X nick end labeling colocalization clearly established a link between apoptosis and caspase-1 expression. Caspase-9 and caspase-3 were activated in caspase-1 overexpressing A2780 cells, suggesting involvement of an intrinsic apoptotic pathway. Caspase-1 overexpression did not change the apoptotic effect of cisplatin in A2780 and OVCAR10 cells, suggesting that this agent activates a different pathway. Immunohistochemically, caspase-1 was lower in ovarian serous carcinomas than in OSE. Our study indicates, for the first time, that caspase-1 is proapoptotic in ovarian cancer cells, and raises the possibility that its down-regulation is one of the mechanisms which increase resistance to apoptosis in cancer cells.