Please use this identifier to cite or link to this item: http://repositorio.unicamp.br/jspui/handle/REPOSIP/340187
Type: Artigo
Title: Genetic and pharmacological inhibition of fatty acid synthase (FASN) attenuates prostate cancer driven by Pten loss
Author: Ribeiro, Caroline F.
Bastos, Debora C.
Pakula, Hubert
Ahearn, Thomas
Nascimento, Jessica
Clohessy, John S.
Mucci, Lorelei
Zanata, Silvio M.
Zadra, Giorgia
Loda, Massimo
Abstract: Inactivation of the tumor suppressor gene phosphatase and tensin homologue (PTEN) is a common alteration in prostate cancer, occurring in the majority of metastatic castration-resistant prostate cancer (mCRPC) cases, and is associated with a more aggressive phenotype and worse prognosis. Another hallmark of prostate cancer is the dysregulation of lipid metabolism with overexpression of fatty acid synthase (FASN), the key enzyme in the de novo synthesis of fatty acids. FASN activity is essential for the generation of new cellular membrane lipids and signaling molecules, conferring growth and survival advantages for cells that overexpress it. Increased FASN expression enhances the aggressive phenotype associated with PTEN loss. To study how inhibition of FASN affects prostate carcinogenesis, we developed a mouse model combining prostate-specific homozygous knockout (KO) of Pten and Fasn genes. Deletion of Fasn, Pten or Fasn/Pten was achieved by expressing Cre recombinase under the control of a Probasin promoter, generating different genotypes: PtenloxP/loxPFasnwt/wtCrepos (P-KO), Ptenwt/wtFasnloxP/loxPCrepos (F-KO) and PtenloxP/loxPFasnloxP/loxPCrepos (F/P-dKO). Inhibition of FASN decreased the weight and volume of the ventral and anterior lobes of murine prostate when compared with Pten single KO mice. Histopathological analysis of the tissues also revealed a reduction in reactive stroma in the ventral and anterior lobes of F/P-dKO in comparison to the P-KO group. This phenotype is suggestive of inhibition of microinvasion. To assess whether FASN inhibition impairs cancer aggressiveness, we tested a novel FASN inhibitor compound, IPI-9119 (Infinity Pharmaceuticals), in epithelial cells from prostate of mice heterozygous for Pten loss. Pharmacological inhibition of de novo lipogenesis lead to decreased cell proliferation and reduction in invasion and motility. Finally, combined loss of PTEN with FASN overexpression assessed in 660 prostate cancer patients with 14.2 years of median follow up, was associated with lethality. Taken together, these data suggest that endogenous lipogenesis supports invasion in a PTEN null background. Since de novo lipogenesis contributes to the aggressive phenotype induced by PTEN loss in murine prostate, targeting lipid metabolism may represent an attractive therapeutic strategy in the context of prostate cancer driven by PTEN loss
Subject: Neoplasias da próstata
Country: Estados Unidos
Editor: American Association for Cancer Research
Rights: Fechado
Identifier DOI: 10.1158/1538-7445.AM2019-3591
Address: https://cancerres.aacrjournals.org/content/79/13_Supplement/3591
Date Issue: 2019
Appears in Collections:FOP - Artigos e Outros Documentos

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