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  • Title: Endometrial cancer cell survival and apoptosis is regulated by protein kinase C alpha and delta.
    Author: Haughian JM, Jackson TA, Koterwas DM, Bradford AP.
    Journal: Endocr Relat Cancer; 2006 Dec; 13(4):1251-67. PubMed ID: 17158769.
    Abstract:
    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 PKCalpha and delta in human endometrial tumors. To determine the functional roles of PKCalpha and delta 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 PKCdelta suppressed etoposide-induced apoptosis, while overexpression of PKCdelta enhanced it. In contrast, inhibition of PKCalpha elevated basal levels of apoptosis and potentiated etoposide-induced cell death. Etoposide treatment also selectively activated PKCdelta, but resulted in both cytosolic translocation and decreased activity of PKCalpha. A fraction of PKCdelta 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 PKCdelta is required for DNA damage-induced apoptosis, while PKCalpha mediates a survival response. Thus, PKCalpha and delta expression and signaling may be important in endometrial tumorigenesis and could serve as potential prognostic indicators and/or novel targets for therapeutic intervention.
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