Title | Overexpression of fatty acid synthase is associated with palmitoylation of Wnt1 and cytoplasmic stabilization of beta-catenin in prostate cancer. |
Publication Type | Journal Article |
Year of Publication | 2008 |
Authors | Fiorentino M, Zadra G, Palescandolo E, Fedele G, Bailey D, Fiore C, Nguyen PL, Migita T, Zamponi R, Di Vizio D, Priolo C, Sharma C, Xie W, Hemler ME, Mucci L, Giovannucci E, Finn S, Loda M |
Journal | Lab Invest |
Volume | 88 |
Issue | 12 |
Pagination | 1340-8 |
Date Published | 2008 Dec |
ISSN | 1530-0307 |
Keywords | Animals, Base Sequence, beta Catenin, Cell Line, Transformed, Cytoplasm, DNA Primers, Fatty Acid Synthases, Humans, Immunohistochemistry, Male, Mice, Mice, Nude, Palmitic Acid, Prostatic Neoplasms, RNA Interference, Wnt1 Protein |
Abstract | Fatty acid synthase (FASN), a key metabolic enzyme for liponeogenesis highly expressed in several human cancers, displays oncogenic properties such as resistance to apoptosis and induction of proliferation when overexpressed. To date, no mechanism has been identified to explain the oncogenicity of FASN in prostate cancer. We generated immortalized prostate epithelial cells (iPrECs) overexpressing FASN, and found that (14)C-acetate incorporation into palmitate synthesized de novo by FASN was significantly elevated in immunoprecipitated Wnt-1 when compared to isogenic cells not overexpressing FASN. Overexpression of FASN caused membranous and cytoplasmic beta-catenin protein accumulation and activation, whereas FASN knockdown by short-hairpin RNA resulted in a reduction in the extent of beta-catenin activation. Orthotopic transplantation of iPrECs overexpressing FASN in nude mice resulted in invasive tumors that overexpressed beta-catenin. A strong significant association between FASN and cytoplasmic (stabilized) beta-catenin immunostaining was found in 862 cases of human prostate cancer after computerized subtraction of the membranous beta-catenin signal (P<0.001, Spearman's rho=0.33). We propose that cytoplasmic stabilization of beta-catenin through palmitoylation of Wnt-1 and subsequent activation of the pathway is a potential mechanism of FASN oncogenicity in prostate cancer. |
DOI | 10.1038/labinvest.2008.97 |
Alternate Journal | Lab Invest |
PubMed ID | 18838960 |
PubMed Central ID | PMC3223737 |
Grant List | P01CA89021 / CA / NCI NIH HHS / United States P50 CA090381 / CA / NCI NIH HHS / United States GM38903 / GM / NIGMS NIH HHS / United States P01 CA055075 / CA / NCI NIH HHS / United States R01CA131945 / CA / NCI NIH HHS / United States CA55075 / CA / NCI NIH HHS / United States R01 CA131945 / CA / NCI NIH HHS / United States R01 CA131945-01A1 / CA / NCI NIH HHS / United States R01 GM038903 / GM / NIGMS NIH HHS / United States P01 CA089021 / CA / NCI NIH HHS / United States P50 CA90381 / CA / NCI NIH HHS / United States |
Related Faculty:
Massimo Loda, M.D.