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Division of Basic Reproductive Sciences, Department of Obstetrics and Gynecology, University of Colorado Health Sciences Center at Fitzsimons, Mail Stop 8309, PO Box 6511 12800 E. 19th Avenue, Aurora, Colorado 80045, USA

(Requests for offprints should be addressed to A P Bradford; Email: andy.bradford{at}uchsc.edu)

Endometrial cancer is the most common invasive gynecologic malignancy but the molecular mechanisms underlying its onset and progression are poorly understood. Paradoxically, endometrial tumors exhibit increased apoptosis, correlating with disease progression and poor patient prognosis. Endometrial tumors also show altered activity and expression of protein kinase C (PKC) isoforms, implicated in the regulation of programmed cell death; however, PKC modulation of apoptosis in endometrial cancer cells has not been investigated. We detected nine out of ten PKC isoforms in Ishikawa endometrial cancer cell lines, and demonstrated expression of both PKC and in human endometrial tumors. To determine the functional roles of PKC and in apoptosis in endometrial cancer, Ishikawa cells were treated with selective PKC inhibitors or adenoviral constructs encoding wild-type or isoform-specific, dominant-negative mutants. Apoptosis was assessed by DNA fragmentation and caspase-mediated poly-(ADP-ribose)-polymerase cleavage. The inhibition of PKC suppressed etoposide-induced apoptosis, while overexpression of PKC enhanced it. In contrast, inhibition of PKC elevated basal levels of apoptosis and potentiated etoposide-induced cell death. Etoposide treatment also selectively activated PKC, but resulted in both cytosolic translocation and decreased activity of PKC. A fraction of PKC also underwent caspase-dependent cleavage, in response to etoposide. Our results suggest that changes in apoptosis and PKC expression in endometrial cancer are mechanistically linked, such that PKC is required for DNA damage-induced apoptosis, while PKC mediates a survival response. Thus, PKC and expression and signaling may be important in endometrial tumorigenesis and could serve as potential prognostic indicators and/or novel targets for therapeutic intervention.