Caveolin-1 in oncogenic transformation, cancer, and metastasis

Abstract

Caveolae are 50- to 100-nm omega-shaped invaginations of the plasma membrane that function as regulators of signal transduction. Caveolins are a class of oligomeric structural proteins that are both necessary and sufficient for caveolae formation. Interestingly, caveolin-1 has been implicated in the pathogenesis of oncogenic cell transformation, tumorigenesis, and metastasis. Here, we review the available experimental evidence (gleaned from cultured cells, animal models, and human tumor samples) that caveolin-1 (Cav-1) functions as a "tumor and/or metastasis modifier gene." Genetic evidence from the study of Cav-1(-/-) null mice and human breast cancer mutations [CAV-1 (P132L)] supports the idea that caveolin-1 normally functions as a negative regulator of cell transformation and mammary tumorigenesis. In contrast, caveolin-1 may function as a tumor promoter in prostate cancers. We discuss possible molecular mechanisms to explain these intriguing, seemingly opposing, findings. More specifically, caveolin-1 phosphorylation (at Tyr14 and Ser80) and mutations (P132L) may override or inactivate the growth inhibitory activity of the caveolin-scaffolding domain (residues 82-101).

Dasatinib, an orally active small molecule inhibitor of both the src and abl kinases, selectively inhibits growth of basal-type/“triple-negative” breast cancer cell lines growing in vitro

“…Caveolin-1 interacts closely with the src family kinase (SFK), fyn, in linking integrins with ras-ERK signaling in the focal adhesion pathway as well as other SFKs [32,33]. Moesin is a member of the ERM (Ezrin/ Radixin/Moesin) family of proteins which have been shown to interact with src in adhesion-mediated signaling [34,35].…”

Growth of hormone-dependent MCF-7 breast cancer cells is promoted by constitutive caveolin-1 whose expression is lost in an EGF-R-mediated manner during development of tamoxifen resistance

“…This dual activity is typified in breast cancer, where the influence of caveolin-1 expression on disease progression appears both type and stage specific [35][36][37]. The use of cell lines derived from breast carcinomas [18,22,38] together with the development and study of caveolin-1 knockout mice [39][40][41] have concluded that the loss of caveolin-1 in mammary epithelial cells is sufficient to drive several pathological features of breast cancer.…”

“…Previous studies [35][36][37] have used recombinant expression of caveolin-1 to restore caveolin-1 levels in various experimental cancer models in order to inhibit oncogenic signalling pathways, including the EGF-R/ERK cascade. Here we examined if the restoration of caveolin-1 in TAM-R cells through recombinant means was sufficient to inhibit EGF-R/ERK signalling, a key driver of the tamoxifenresistant phenotype in this cell model.…”

p38 MAPK activation coupled to endocytosis is a determinant of endothelial monolayer integrity

“…There is a constitutive process of endocytosis mediated by the internalization of the plasmalemmal invaginations, caveolae (20). Although caveolar internalization is responsible for transcytosis of albumin and other plasma proteins across the endothelial barrier, endocytosis may also have key functions in cell signaling (4,5,7,25). In the present study, we investigated the possibility that caveolae-mediated endocytosis is a determinant of endothelial cell proliferation and cell survival and thus regulates the integrity of the endothelial monolayer.…”

“…Endocytosis was assayed by the uptake of albumin with FITC-BSA or TRITC-BSA as the tracer (24). In RLM-VEC treated with the MAPK p38 inhibitor SB-203580 (6,7,25) (Calbiochem, San Diego, CA), the drug (1-20 M) was incubated in increasing concentrations in confluent cell monolayers for 4 h at 37°C. Care was taken to avoid exposure to light during the uptake assay.…”