Caveolin-1 interacts with a lipid raft-associated population of fatty acid synthase.
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.
Di Vizio
Dolores
D
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
Adam
Rosalyn M
RM
Kim
Jayoung
J
Kim
Robert
R
Sotgia
Federica
F
Williams
Terence
T
Demichelis
Francesca
F
Solomon
Keith R
KR
Loda
Massimo
M
Rubin
Mark A
MA
Lisanti
Michael P
MP
Freeman
Michael R
MR
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
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)