期刊
INTERNATIONAL JOURNAL OF CANCER
卷 125, 期 11, 页码 2556-2564出版社
WILEY
DOI: 10.1002/ijc.24633
关键词
PKC; endometrial cancer; Akt; p21; p27
类别
资金
- NCI [CA 104875]
- University of Colorado Cancer Center's Cytogenesis and Flow Cytometry Core
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, PKC alpha, in an established cell model of endometrial adenocarcinoma. Ishikawa cells depleted of PKC alpha protein grew slower, formed fewer colonies in anchorage-independent growth assays and exhibited impaired xenograft tumor formation in nude mice. Consistent with impaired growth, PKC alpha 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, PKC alpha knockdown reduced Akt phosphorylation at serine 473 and concomitantly inhibited phosphorylation of the Akt target, glycogen synthase kinase-3 beta (GSK-3 beta). PKC alpha 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 PKC alpha regulates CDK expression independently of Akt and ERK. Immunohistochemical analysis of Grade 1 endometrioid adenocarcinoma revealed aberrant PKC alpha expression, with foci of elevated PKC alpha staining, not observed in normal endometrium. These studies demonstrate a critical role for PKC alpha signaling in endometrial tumorigenesis by regulating expression of CDK inhibitors p21 and p27 and activation of Akt and ERK-dependent proliferative pathways. Thus, targeting PKC alpha may provide novel therapeutic options in endometrial tumors. (c) 2009 UICC
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