Premium
Function of Caveolin‐1 in Paclitaxel‐mediated Cytotoxicity in Breast Cancer
Author(s) -
Shajahan Ayesha N.,
Wang Aifen,
Minshall Richard D.,
Liu Minetta C.,
Clarke Robert
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.5.a437
Subject(s) - phosphorylation , paclitaxel , apoptosis , cancer research , tyrosine phosphorylation , taxane , biology , microbiology and biotechnology , cancer cell , breast cancer , chemistry , cancer , biochemistry , genetics
Breast cancer is the most common cancer in women in the U.S. In primary breast cancer cells, expression of caveolin‐1 (CAV1), a putative regulator of cellular transformation, is down‐regulated. In addition to membranes, CAV1 also 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 but it is unknown how down‐regulation of CAV1 affects paclitaxel sensitivity. We show that phosphorylation of CAV1 on Tyr 14 regulates paclitaxel‐mediated apoptosis in MCF‐7 breast cancer cells. CAV1 sensitizes cells to apoptosis by regulating cell cycle progression and activation of apoptotic signaling molecules BCL2, p53 and p21. Phosophorylated CAV1 triggers apoptosis by inactivating BCL2 and increasing mitochondrial permeability more efficiently than non‐phosophorylated CAV1. Furthermore, expression of p21 that correlates with taxane sensitivity is regulated by CAV1 phosphorylation in a p53‐dependent manner. 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. ANS is supported by a Fellowship from the Susan G. Komen Breast Cancer Foundation .