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Protein kinase C alpha-dependent signaling mediates endometrial cancer cell growth and tumorigenesis

✍ Scribed by James M. Haughian; Elaine M. Reno; Alicia M. Thorne; Andrew P. Bradford

Publisher
John Wiley and Sons
Year
2009
Tongue
French
Weight
573 KB
Volume
125
Category
Article
ISSN
0020-7136

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✦ Synopsis

Abstract

Endometrial cancer is the most common invasive gynecologic malignancy, yet molecular mechanisms and signaling pathways underlying its etiology and pathophysiology remain poorly characterized. We sought to define a functional role for the protein kinase C (PKC) isoform, PKCα, in an established cell model of endometrial adenocarcinoma. Ishikawa cells depleted of PKCα protein grew slower, formed fewer colonies in anchorage‐independent growth assays and exhibited impaired xenograft tumor formation in nude mice. Consistent with impaired growth, PKCα knockdown increased levels of the cyclin‐dependent kinase (CDK) inhibitors p21^Cip1/WAF1^ (p21) and p27^Kip1^ (p27). Despite the absence of functional phosphatase and tensin homolog (PTEN) protein in Ishikawa cells, PKCα knockdown reduced Akt phosphorylation at serine 473 and concomitantly inhibited phosphorylation of the Akt target, glycogen synthase kinase‐3β (GSK‐3β). PKCα knockdown also resulted in decreased basal ERK phosphorylation and attenuated ERK activation following EGF stimulation. p21 and p27 expression was not increased by treatment of Ishikawa cells with ERK and Akt inhibitors, suggesting that PKCα regulates CDK expression independently of Akt and ERK. Immunohistochemical analysis of Grade 1 endometrioid adenocarcinoma revealed aberrant PKCα expression, with foci of elevated PKCα staining, not observed in normal endometrium. These studies demonstrate a critical role for PKCα signaling in endometrial tumorigenesis by regulating expression of CDK inhibitors p21 and p27 and activation of Akt and ERK‐dependent proliferative pathways. Thus, targeting PKCα may provide novel therapeutic options in endometrial tumors. © 2009 UICC

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