This Article Full Text Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Bae, K.-M. Articles by Xiao, L. Search for Related Content PubMed PubMed Citation Articles by Bae, K.-M. Articles by Xiao, L.

Protein Kinase C Is Overexpressed in Primary Human Non–Small Cell Lung Cancers and Functionally Required for Proliferation of Non–Small Cell Lung Cancer Cells in a p21/Cip1-Dependent Manner

¹ University of Florida Shands Cancer Center, ² Department of Anatomy and Cell Biology, and ³ Department of Pathology, Immunology and Laboratory Medicine, University of Florida College of Medicine, Gainesville, Florida

Requests for reprints: Lei Xiao, University of Florida Shands Cancer Center, 1376 Mowry Road, P.O. Box 103633, Gainesville, FL 32610-3633. Phone: 352-273-8168; Fax: 352-273-8109; E-mail: lxiao{at}ufl.edu.

The protein kinase C (PKC) family of proteins plays important roles in growth regulation and is implicated in tumorigenesis. It has become clear that the role of PKC in tumorigenesis is cell context dependent and/or isoform specific. In this study, we showed for the first time by immunohistochemistry that overexpression of PKC was detected in the vast majority (>90%) of primary human non–small cell lung cancers (NSCLC) compared with normal lung epithelium. Inhibition of the PKC pathway using a kinase-inactive, dominant-negative PKC, PKC(KR), led to a significant inhibition of proliferation and anchorage-independent growth of human NSCLC cells in a p53-independent manner. This was accompanied by a specific induction of the cyclin-dependent kinase (cdk) inhibitor p21/Cip1 but not p27/Kip1. In response to serum stimulation, PKC(KR)-expressing cells showed a prolonged G₁-S transition and delayed and reduced activation of cdk2 complexes, which was likely attributed to the increased binding of p21/Cip1 to cdk2. Furthermore, inhibition of PKC function either by expressing PKC(KR) or by small interfering RNA (siRNA)–mediated gene knockdown resulted in c-Myc down-regulation, which, in turn, regulated p21/Cip1 expression. Knockdown of PKC or c-Myc expression using siRNA led to induction of p21/Cip1 and attenuation of G₁-S transition in NSCLC cells. Using p21^+/+ and p21^–/– HCT116 isogenic cell lines, we further showed that growth inhibition by PKC(KR) required the function of p21/Cip1. Collectively, these results reveal an important role for PKC signaling in lung cancer and suggest that one potential mechanism by which PKC exerts its oncogenic activity is through deregulation of the cell cycle via a p21/Cip1–dependent mechanism. [Cancer Res 2007;67(13):6053–63]

This article has been cited by other articles:

				U. Gundimeda, J. E. Schiffman, D. Chhabra, J. Wong, A. Wu, and R. Gopalakrishna Locally Generated Methylseleninic Acid Induces Specific Inactivation of Protein Kinase C Isoenzymes: RELEVANCE TO SELENIUM-INDUCED APOPTOSIS IN PROSTATE CANCER CELLS J. Biol. Chem., December 12, 2008; 283(50): 34519 - 34531. [Abstract] [Full Text] [PDF]

				M-Y. Li, J. Yip, M. K. Y. Hsin, T. S. K. Mok, Y. Wu, M. J. Underwood, and G. G. Chen Haem oxygenase-1 plays a central role in NNK-mediated lung carcinogenesis Eur. Respir. J., October 1, 2008; 32(4): 911 - 923. [Abstract] [Full Text] [PDF]