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 Jin, Y. Articles by Rao, J. Search for Related Content PubMed PubMed Citation Articles by Jin, Y. Articles by Rao, J.

Research Articles: Therapeutics

Effect of an epidermal growth factor receptor tyrosine kinase inhibitor on actin remodeling in an in vitro bladder cancer carcinogenesis model

Departments of ¹ Pathology and Laboratory Medicine, ² Urology, ³ Medicine, and ⁴ Epidemiology, University of California at Los Angeles, Los Angeles, California; ⁵ OSI Pharmaceuticals, Inc., New York, New York; and ⁶ Division of Cancer Prevention, National Cancer Institute, Bethesda, Maryland

Requests for reprints: Jianyu Rao, Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California at Los Angeles, Box 951732, Los Angeles, CA 90095-1732. Phone: 310-794-1567; Fax: 310-206-5178. E-mail: jrao{at}mednet.ucla.edu

Alteration of actin remodeling is a marker of malignant-associated field defect and a potential surrogate biomarker for chemoprevention trials. We tested erlotinib, a specific tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR), on actin remodeling in a bladder carcinogenic model consisting of untransformed HUC-PC cells and transformed MC-T11 cells, both derived from the same normal human urothelial clone immortalized by SV40. Erlotinib had a selective growth inhibitory and actin remodeling effect on MC-T11 cells over HUC-PC cells, as examined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and immunofluorescence labeling with laser scan cytometer analysis, respectively. The IC₅₀ of untransformed HUC-PC cells was significantly higher than that of transformed MC-T11 cells (P < 0.05, t test). The actin remodeling effect was more prominent at lower dosage levels (1/8-1/4 of IC₅₀), which was accompanied by an increased cell adhesion and decreased motility. At higher dosage levels (1/2 of IC₅₀), erlotinib induced a decreased adhesion and anoikis (detachment-associated apoptosis). The transformed MC-T11, but not HUC-PC, showed a weak constitutive EGFR phosphorylation activity, which was inhibited by erlotinib in a dose-response manner. However, on epidermal growth factor stimulation, both cell lines showed a similar dose-response inhibitory effect on phosphorylated EGFR and mitogen-activated protein kinase (MAPK; P44/P42) activities, and MAPK inhibitor PD98059 showed no specific effect on erlotinib-induced actin remodeling, suggesting that pathways other than MAPK (P44/P42) may be responsible for erlotinib-induced actin remodeling. The findings provide evidence to support erlotinib-based bladder cancer chemoprevention and using actin remodeling as a marker for erlotinib-based intervention trials. [Mol Cancer Ther 2006;5(7):1754–63]

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 1/25/06; revised 5/ 1/06; accepted 5/12/06.

This article has been cited by other articles:

				A. B. Singh, K. Sugimoto, and R. C. Harris Juxtacrine Activation of Epidermal Growth Factor (EGF) Receptor by Membrane-anchored Heparin-binding EGF-like Growth Factor Protects Epithelial Cells from Anoikis While Maintaining an Epithelial Phenotype J. Biol. Chem., November 9, 2007; 282(45): 32890 - 32901. [Abstract] [Full Text] [PDF]