Caveolin-1 Tyrosine Phosphorylation Enhances Paclitaxel-mediated Cytotoxicity

Abstract

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 G 2 /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. Caveolin-1 (CAV1)2 is a 21-24-kDa protein and the prototype of a family of integral membrane proteins that associate with specific cholesterol-and sphingolipid-rich domains to form the structural foundation of membrane invaginations called caveolae. Caveolae act as sites of signal transduction in various cell types (1). CAV1 is thought to regulate the activity of proteins such as Src kinases, epidermal growth factor tyrosine kinase, Her2/neu (ErbB2) kinase, ERK (extracellular signal-regulated kinase), H-Ras, endothelial nitric-oxide synthase, and G proteins (1, 2) involved in survival pathways. In human breast tumors, CAV1 levels inversely correlate with tumor size (3), and CAV1 expression reduces the growth of mouse mammary tumors and their spontaneous metastasis to lung and bone (4). However, in breast cancer cell culture models, CAV1 is downregulated in non-invasive human breast cancer cells but upregulated in cells with an invasive phenotype (5-7).Taxanes are potent anti-tumor agents that function by binding to the ␤ subunits of tubulin and repressing the dynamic instability of spindles (8, 9), activities that lead to cell cycle arrest in the G 2 /M phase (10). Taxanes such as paclitaxel (Taxol) or docetaxel (Taxotere) are routinely used in the firstline treatment of metastatic breast, lung, ovarian, and digestive cancers (11). In primary breast cancer, inclusion of taxane in adjuvant chemotherapy reduces the relative risk of recurrence and improves overall survival (12). Acquired resistance through cellular adaptations or mutations in neoplastic cells remains a major problem in chemotherapy. Although taxanes are substrates for ABC transporters, other resistance mechanis...

CSE1L/CAS, a microtubule-associated protein, inhibits taxol (paclitaxel)-induced apoptosis but enhances cancer cell apoptosis induced by various chemotherapeutic drugs

“…The association of the microtubule-associated protein with microtubules in tumor cells may affect the sensitivity of cancer cells to paclitaxel-induced apoptosis. Caveolin-1 has been reported to be associated with microtubules and to enhance paclitaxel-mediated apoptosis of MCF-7 cells (29). Low expression of the microtubule-binding protein, tau, was reported to enhance the sensitivity of human breast cancer to http://bmbreports.org paclitaxel treatment (30).…”

Downregulation of caveolin-1 increases the sensitivity of drug-resistant colorectal cancer HCT116 cells to 5-fluorouracil

“…Cav-1, as the principal component of caveolae, plays an important role in material transportation, endothelial infiltration and tumorigenesis (18). Cav-1 acts as a scaffolding protein by interacting with signaling molecules through a caveolin scaffolding domain to modulate gene expression, signal transduction and protein translocation in the cell membrane (18 invasion and metastasis (19)(20)(21)(22). Additionally, it has been shown that Cav-1 is closely associated with the development of drug resistance (23)(24)(25).…”

Immunohistochemical and molecular analysis of caveolin-1 expression in canine mammary tumors

“…Caveolin-1 (Cav-1) is a structural protein of 50 to 100 nm present in invaginations of the cell membrane (caveolae) (Bat'ová et al, 2003;Williams and Lisanti, 2005;Sotgia et al, 2006;Williams et al, 2006;Shajahan et al, 2007). Caveolae are enriched by sphingolipids and cholesterol (Zhu et al, 2008) and are directly involved in vesicular trafficking and signal transduction (Bouras et al, 2004;Chen et al, 2004;Elsheikh et al, 2008).…”