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Originally published In Press as doi:10.1074/jbc.M205002200 on August 7, 2002

J. Biol. Chem., Vol. 277, Issue 41, 38978-38987, October 11, 2002
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Dual Inhibition of Focal Adhesion Kinase and Epidermal Growth Factor Receptor Pathways Cooperatively Induces Death Receptor-mediated Apoptosis in Human Breast Cancer Cells*

Vita GolubovskayaDagger §, Lucia BevigliaDagger , Li-Hui XuDagger §, H. Shelton Earp IIIDagger , Rolf CravenDagger §, and William CanceDagger §||**

From the Dagger  Lineberger Comprehensive Cancer Center, School of Medicine, and the Departments of || Cell and Developmental Biology and § Surgery, University of North Carolina, Chapel Hill, North Carolina 27599

The focal adhesion kinase (FAK) and epidermal growth factor receptor (EGFR) are protein-tyrosine kinases that are overexpressed and activated in human breast cancer. To determine the role of EGFR and FAK survival signaling in breast cancer, EGFR was stably overexpressed in BT474 breast cancer cells, and each signaling pathway was specifically targeted for inhibition. FAK and EGFR constitutively co-immunoprecipitated in EGFR-overexpressing BT474 cells. In low EGFR-expressing BT474-pcDNA3 vector control cells, inhibition of FAK by the FAK C-terminal domain caused detachment and apoptosis via pathways involving activation of caspase-3 and -8, cleavage of poly(ADP-ribose) polymerase, and caspase-3-dependent degradation of AKT. This apoptosis could be rescued by the dominant-negative Fas-associated death domain, indicating involvement of the death receptor pathway. EGFR overexpression did not inhibit detachment induced by the FAK C-terminal domain, but did suppress apoptosis, activating AKT and ERK1/2 survival pathways and inhibiting cleavage of FAK, caspase-3 and -8, and poly(ADP-ribose) polymerase. Furthermore, this protective effect of EGFR signaling was reversed by EGFR kinase inhibition with AG1478. In addition, inhibition of FAK and EGFR in another breast cancer cell line (BT20) endogenously overexpressing these kinases also induced apoptosis via the same mechanism as in the EGFR-overexpressing BT474 cells. The results of this study indicate that dual inhibition of FAK and EGFR signaling pathways can cooperatively enhance apoptosis in breast cancers.

* This work was supported by NCI Grant CA65910 from the National Institutes of Health (to W. C.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Building Interdisciplinary Research Careers in Women's Health Scholar from the National Institutes of Health.

** To whom correspondence should be addressed: Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina, CB 7210, 3010 Old Clinic Bldg., Chapel Hill, NC 27599. Tel.: 919-966-5221; Fax: 919-966-8806; E-mail: cance@med.unc.edu.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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