This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services 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 Stallings-Mann, M. Articles by Fields, A. P. Search for Related Content PubMed PubMed Citation Articles by Stallings-Mann, M. Articles by Fields, A. P.

A Novel Small-Molecule Inhibitor of Protein Kinase C Blocks Transformed Growth of Non–Small-Cell Lung Cancer Cells

Department of Cancer Biology, Mayo Clinic College of Medicine, Jacksonville, Florida

Requests for reprints: Alan P. Fields, Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, Room 312, Griffin Cancer Research Building, 4500 San Pablo Road, Jacksonville, FL 32224. Phone: 904-953-6160; Fax: 904-953-0277; E-mail: fields.alan{at}mayo.edu.

We recently showed that atypical protein kinase C (PKC) is required for transformed growth of human non–small-cell lung cancer (NSCLC) cells by activating Rac1. Genetic disruption of PKC signaling blocks Rac1 activity and transformed growth, indicating that PKC is a viable target for development of novel therapeutics for NSCLC. Here, we designed and implemented a novel fluorescence resonance energy transfer–based assay to identify inhibitors of oncogenic PKC signaling. This assay was used to identify compounds that disrupt the interaction between PKC and its downstream effector Par6, which links PKC to Rac1. We identified aurothioglucose (ATG), a gold compound used clinically to treat rheumatoid arthritis, and the related compound, aurothiomalate (ATM), as potent inhibitors of PKC-Par6 interactions in vitro (IC₅₀ 1 µmol/L). ATG blocks PKC-dependent signaling to Rac1 and inhibits transformed growth of NSCLC cells. ATG-mediated inhibition of transformation is relieved by expression of constitutively active Rac1, consistent with a mechanism at the level of the interaction between PKC and Par6. ATG inhibits A549 cell tumor growth in nude mice, showing efficacy against NSCLC in a relevant preclinical model. Our data show the utility of targeting protein-protein interactions involving PKC for antitumor drug development and provide proof of concept that chemical disruption of PKC signaling can be an effective treatment for NSCLC. ATG and ATM will be useful reagents for studying PKC function in transformation and represent promising new agents for the clinical treatment of NSCLC. (Cancer Res 2006; 66(3): 1767-74)

This article has been cited by other articles:

				R. P. Regala, E. A. Thompson, and A. P. Fields Atypical Protein Kinase C{iota} Expression and Aurothiomalate Sensitivity in Human Lung Cancer Cells Cancer Res., July 15, 2008; 68(14): 5888 - 5895. [Abstract] [Full Text] [PDF]

				M. Lee and V. Vasioukhin Cell polarity and cancer - cell and tissue polarity as a non-canonical tumor suppressor J. Cell Sci., April 15, 2008; 121(8): 1141 - 1150. [Abstract] [Full Text] [PDF]

				E. Erdogan, T. Lamark, M. Stallings-Mann, Lee Jamieson, M. Pellechia, E. A. Thompson, T. Johansen, and A. P. Fields Aurothiomalate Inhibits Transformed Growth by Targeting the PB1 Domain of Protein Kinase C{iota} J. Biol. Chem., September 22, 2006; 281(38): 28450 - 28459. [Abstract] [Full Text] [PDF]

				B. A. Teicher Protein kinase C as a therapeutic target. Clin. Cancer Res., September 15, 2006; 12(18): 5336 - 5345. [Full Text] [PDF]