title: Caveolin-1 interacts with a lipid raft-associated population of fatty acid synthase.
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-1(C133/143/156S), that prevents phosphorylation by Src, did not interact with FASN. When overexpressed in Cav-1-negative PCa cells, Cav-1(C133/143/156S) 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.
authors.affiliation: The Urological Diseases Research Center and Department of Surgery, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts 02115, USA. dolores.divizio@childrens.harvard.edu
authors.forename: Dolores
authors.initials: D
authors.lastname: Di Vizio
authors.forename: Rosalyn M
authors.initials: RM
authors.lastname: Adam
authors.forename: Jayoung
authors.initials: J
authors.lastname: Kim
authors.forename: Robert
authors.initials: R
authors.lastname: Kim
authors.forename: Federica
authors.initials: F
authors.lastname: Sotgia
authors.forename: Terence
authors.initials: T
authors.lastname: Williams
authors.forename: Francesca
authors.initials: F
authors.lastname: Demichelis
authors.forename: Keith R
authors.initials: KR
authors.lastname: Solomon
authors.forename: Massimo
authors.initials: M
authors.lastname: Loda
authors.forename: Mark A
authors.initials: MA
authors.lastname: Rubin
authors.forename: Michael P
authors.initials: MP
authors.lastname: Lisanti
authors.forename: Michael R
authors.initials: MR
authors.lastname: Freeman
mesh_terms: D000818:Animals; D051242:Caveolin 1 / Q000378:metabolism*; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000187:drug effects; D064429:Fatty Acid Synthases / Q000378:metabolism*; D006801:Humans; D008297:Male; D021962:Membrane Microdomains / Q000187:drug effects / Q000201:enzymology*; D051379:Mice; D009154:Mutation / Q000235:genetics; D019308:Palmitic Acid / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011467:Prostate / Q000201:enzymology / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D021381:Protein Transport / Q000187:drug effects; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D051242:Caveolin 1; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D019308:Palmitic Acid; D064429:Fatty Acid Synthases; D016392:Proto-Oncogene Proteins pp60(c-src)