Caveolin-1 interacts with a lipid raft-associated population of fatty acid synthase

Dolores Di Vizio, Rosalyn M. Adam, Jayoung Kim, Robert Kim, Federica Sotgia, Terence Williams, Francesca Demichelis, Keith R. Solomon, Massimo Loda, Mark A. Rubin, Michael P. Lisanti, Michael R. Freeman

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    Abstract

    Fatty Acid Synthase (FASN), a cytoplasmic biosynthetic enzyme, is the major source of long-chain fatty acids, particularly palmitate. Caveolin-1 (Cav-1) is a palmitoylated lipid raft protein that plays a key role in signal transduction and cholesterol transport. Both proteins have been implicated in prostate cancer (PCa) progression, and Cav-1 regulates FASN expression in a mouse model of aggressive PCa. We demonstrate that FASN and Cav-1 are coordinately upregulated in human prostate tumors in a hormone-insensitive manner. Levels of FASN and Cav-1 protein expression discriminated between localized and metastatic cancers, and the two proteins exhibited analogous subcellular locations in a tumor subset. Endogenous FASN and Cav-1 were reciprocally co-immunoprecipitated from human and murine PCa cells, indicating that FASN forms a complex with Cav-1. FASN, a cytoplasmic enzyme, was induced to associate transiently with lipid raft membranes following alterations in signal transduction within the Src, Akt and EGFR pathways, suggesting that co-localization of FASN and Cav-1 is dependent on activation of upstream signaling mediators. A Cav-1 palmitoylation mutant, Cav-1C133/143/156S, that prevents phosphorylation by Src, did not interact with FASN. When overexpressed in Cav-1-negative PCa cells, Cav-1C133/143/156S caused a reduction of both Src and Akt levels, as well as of their active, phosphorylated forms, in comparison with wild type Cav-1. These findings suggest that FASN and Cav-1 physically and functionally interact in PCa cells. They also imply that palmitoylation within this complex is involved in tumor growth and survival. ©2008 Landes Bioscience.
    Original languageEnglish
    Pages (from-to)2257-2267
    Number of pages10
    JournalCell Cycle
    Volume7
    Issue number14
    DOIs
    Publication statusPublished - 15 Jul 2008

    Keywords

    • Caveolin-1
    • Fatty acid synthase
    • Lipid raft membranes
    • Prostate cancer

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