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First published on July 6, 2006; DOI: 10.1124/mol.106.026195

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Received for publication May 3, 2006.
Revised July 5, 2006.
Accepted for publication July 6, 2006.

Focal adhesion kinase (FAK) and protein kinase B cooperate to suppress doxorubicin-induced apoptosis of breast tumor cells

Maroesja J van Nimwegen 1, Merei Huigsloot 1, Annamarie Camier 1, Ine B Tijdens 1, Bob van de Water 2*

1 LACDR 2 Leiden University

* Address correspondence to: E-mail: b.water{at}lacdr.leidenuniv.nl

Abstract

Abstract Focal adhesion kinase (FAK) is upregulated in a variety of cancers including breast cancer, in association with poor disease prognosis. In the present study we examined the role of focal adhesion kinase (FAK) in the control of anticancer drug-induced apoptosis of mammary adenocarcinoma MTLn3 cells. Doxorubicin caused formation of well-defined focal adhesions and stress fibers early after treatment, which was later followed by their loss in association with the onset of apoptosis. Phosphorylation of FAK on tyrosine 397 decreased only during the onset of doxorubicin-induced apoptosis, in a Bcl-2 and caspase-independent manner. Doxorubicin also caused an early activation of protein kinase B (PKB). Expression of the dominant negative acting focal adhesion kinase-related non-kinase (FRNK) sensitized MTLn3 cells to apoptosis caused by doxorubicin. FRNK inhibited the doxorubicin-induced activation of PKB. Also, inhibition of phosphatidylinositide-3 (PI-3) kinase with wortmannin inhibited the activation of PKB by doxorubicin. Both wortmannin as well as transient overexpression of the dual lipid/protein phosphatase PTEN enhanced doxorubicin-induced cell death. Altogether these data fit with a model wherein FAK is involved in the doxorubicin-induced activation of the PI-3 kinase/PKB signaling route, thereby suppressing the onset of apoptosis caused by doxorubicin.


Key words: Src and other nonreceptor tyrosine kinases, Structure/function/mechanism, Apoptosis, Mechanisms of cell killing/apoptosis, Resistance, Tumor suppressors


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