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J. Biol. Chem., Vol. 282, Issue 8, 5934-5943, February 23, 2007

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Caveolin-1 Tyrosine Phosphorylation Enhances Paclitaxel-mediated Cytotoxicity^*

Ayesha N. Shajahan, Aifen Wang, Markus Decker, Richard D. Minshall, Minetta C. Liu, and Robert Clarke^¶1

From the Department of Oncology, Lombardi Comprehensive Cancer Center, and ^¶Departments of Physiology and Biophysics, Georgetown University, College of Medicine, Washington, D. C. 20057 and Departments of Pharmacology and Anesthesiology, University of Illinois at Chicago, Chicago, Illinois 60612

Caveolin-1 (CAV1), a highly conserved membrane-associated protein, is a putative regulator of cellular transformation. CAV1 is localized in the plasmalemma, secretory vesicles, Golgi, mitochondria, and endoplasmic reticulum membrane and associates with the microtubule cytoskeleton. Taxanes such as paclitaxel (Taxol) are potent anti-tumor agents that repress the dynamic instability of microtubules and arrest cells in the G₂/M phase. Src phosphorylation of Tyr-14 on CAV1 regulates its cellular localization and function. We report that phosphorylation of CAV1 on Tyr-14 regulates paclitaxel-mediated apoptosis in MCF-7 breast cancer cells. Befitting its role as a multitasking molecule, we show that CAV1 sensitizes cells to apoptosis by regulating cell cycle progression and activation of the apoptotic signaling molecules BCL2, p53, and p21. We demonstrate that phosphorylated CAV1 triggers apoptosis by inactivating BCL2 and increasing mitochondrial permeability more efficiently than non-phosphorylated CAV1. Furthermore, expression of p21, which correlates with taxane sensitivity, is regulated by CAV1 phosphorylation in a p53-dependent manner. Collectively, our findings underscore the importance of CAV1 phosphorylation in apoptosis and suggest that events that negate CAV1 tyrosine phosphorylation may contribute to anti-microtubule drug resistance.

Received for publication, September 14, 2006 , and in revised form, December 5, 2006.

^* This work was supported by Public Health Service Grant R01-CA096483 and Dept. of Defense Grant BC030280 (to R. C.) and Susan G. Komen Breast Cancer Foundation Postdoctoral Fellowship PDF0600477 (to A. N. S.). Technical services were provided by the Flow Cytometry and Cell Sorting, Tissue Culture Core and Microscopy and Imaging Shared Resources Center funded through Public Health Service Award 1P30-CA-51008 (Lombardi Comprehensive Cancer Center support grant). 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.

¹ To whom correspondence should be addressed: Dept. of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, College of Medicine, 3970 Reservoir Rd. N.W., NRB W405, Washington, D. C. 20057. Tel.: 202-687-7237; Fax: 202-687-7505; E-mail: clarker{at}georgeotown.edu.

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