Analysis of protein kinase C delta (PKCδ) expression in endometrial tumors

Abstract

Endometrial cancer is the most common gynecologic malignancy in the United States. However, its underlying molecular mechanisms are poorly understood; and few prognostic indicators have been identified. The protein kinase C (PKC) family has been shown to regulate pathways critical to malignant transformation; and in endometrial tumors, changes in PKC expression and activity have been linked to a more aggressive phenotype and poor prognosis. We have recently shown that PKC delta is a critical regulator of apoptosis and cell survival in endometrial cancer cells; however, PKC delta levels in endometrial tumors had not been determined. We used immunohistochemistry to examine PKC delta protein levels in normal endometrium and endometrioid carcinomas of increasing grade. Normal endometrium exhibited abundant nuclear and cytoplasmic staining of PKC delta confined to glandular epithelium. In endometrial tumors, decreased PKC delta expression, both in intensity and fraction of epithelial cells stained, was observed with increasing tumor grade, with PKC delta being preferentially lost from the nucleus. Consistent with these observations, endometrial cancer cell lines derived from poorly differentiated tumors exhibited reduced PKC delta levels relative to well-differentiated lines. Treatment of endometrial cancer cells with etoposide resulted in a translocation of PKC delta from cytoplasm to nucleus concomitant with induction of apoptosis. Decreased PKC delta expression, particularly in the nucleus, may compromise the ability of cells to undergo apoptosis, perhaps conferring resistance to chemotherapy. Our results indicate that loss of PKC delta is an indicator of endometrial malignancy and increasing grade of cancer. Thus, PKC delta may function as a tumor suppressor in endometrial cancer.

Protein Arginine Methyltransferase 5 (PRMT5) Signaling Suppresses Protein Kinase Cδ- and p38δ-dependent Signaling and Keratinocyte Differentiation

“…In addition to an important role in normal cells, these findings suggest a role for PRMT5 in skin cancer. PRMT5 levels are increased (29), and PKC␦ levels are decreased in cancer (59,60). Thus, the balance between these signaling inputs is likely to be important in disease development, and we anticipate that PRMT5 may serve to enhance skin cancer cell survival.…”

Loss of Protein Kinase C δ Gene Expression in Human Squamous Cell Carcinomas

“…PKC-␦ protein is also reduced in high grade endometrial and bladder cancers, but the mechanism of PKC␦ loss in these cancers has not been reported. [22][23][24] The PKC-␦ gene has been previously shown to be up-regulated by a variety of transcription factors. [25][26][27][28][29] The mechanism of reduced PKC-␦ gene expression in human SCCs is unknown, but is likely to involve Ras/ EGFR signaling.…”

Protein Kinase Cδ Activates RelA/p65 and Nuclear Factor-κB Signaling in Response to Tumor Necrosis Factor-α

“…It can induce both cell survival and apoptosis depending on cell types and its subcellular localization (2). For instance, treatment with anticancer agents resulted in a translocation of PKCy from cytoplasm into nucleus concomitant with induction of apoptosis (12,19,44). Our recent studies showed PKCy is involved in phosphorylation of p53 and potentiates p53-dependent apoptosis in response to DNA damage (17).…”