Research article summary (published 29 Nov 2009):

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

Full 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, PKCalpha, in an established cell model of endometrial adenocarcinoma. Ishikawa cells depleted of PKCalpha protein grew slower, formed fewer colonies in anchorage-independent growth assays and exhibited impaired xenograft tumor formation in nude mice. Consistent with impaired growth, PKCalpha 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, PKCalpha knockdown reduced Akt phosphorylation at serine 473 and concomitantly inhibited phosphorylation of the Akt target, glycogen synthase kinase-3beta (GSK-3beta). PKCalpha 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 PKCalpha regulates CDK expression independently of Akt and ERK. Immunohistochemical analysis of Grade 1 endometrioid adenocarcinoma revealed aberrant PKCalpha expression, with foci of elevated PKCalpha staining, not observed in normal endometrium. These studies demonstrate a critical role for PKCalpha signaling in endometrial tumorigenesis by regulating expression of CDK inhibitors p21 and p27 and activation of Akt and ERK-dependent proliferative pathways. Thus, targeting PKCalpha may provide novel therapeutic options in endometrial tumors.

Author information

Author/s: Haughian, James M (JM); Reno, Elaine M (EM); Thorne, Alicia M (AM); Bradford, Andrew P (AP);

Affiliation: Department of Obstetrics and Gynecology, Section of Basic Reproductive Sciences, University of Colorado, Denver School of Medicine, Aurora, CO 80045, USA.

Grants: CA 104875 (Agency:NCI NIH HHS)

Journal and publication information

Publication Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't

Journal: International journal of cancer. Journal international du cancer (Int J Cancer), published in United States. (Language: eng)

Reference: 2009-Dec; vol 125 (issue 11) : pp 2556-64

Dates: Created 2009/10/05; Completed 2009/11/06;

PMID: 19672862, status: MEDLINE (last retrieval date: 11/6/2009, IMS Date: )

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

Adenocarcinoma - metabolism; pathology Animals Apoptosis Blotting, Western Cell Cycle Cell Proliferation Colony-Forming Units Assay Cyclin-Dependent Kinase Inhibitor p21 - metabolism Cyclin-Dependent Kinase Inhibitor p27 - metabolism Endometrial Neoplasms - metabolism; pathology Female

Glycogen Synthase Kinase 3 - metabolism Humans Immunoenzyme Techniques Luciferases - metabolism Mice Mice, Nude PTEN Phosphohydrolase - metabolism Phosphorylation Protein Kinase C-alpha - metabolism Proto-Oncogene Proteins c-akt - metabolism Signal Transduction

Associated Chemicals: Cyclin-Dependent Kinase Inhibitor p21 (0) ; Cyclin-Dependent Kinase Inhibitor p27 (147604-94-2) ; Luciferases (EC 1.13.12.-) ; Glycogen Synthase Kinase 3 (EC 2.7.1.37) ; Protein Kinase C-alpha (EC 2.7.1.37) ; Proto-Oncogene Proteins c-akt (EC 2.7.1.37) ; glycogen synthase kinase 3 beta (EC 2.7.1.37) ; PTEN protein, human (EC 3.1.3.48) ; PTEN Phosphohydrolase (EC 3.1.3.67)

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