Abstract 51: Blood pressure lowering medications disrupt fatty acid metabolism in pancreatic cancer

Abstract

Abstract Despite the routine use of chemotherapy and radiotherapy, survival has not significantly improved in patients with pancreatic ductal adenocarcinoma (PDA), a situation that signifies the urgent need for novel therapeutic approaches. Angiotensin II (AngII), the principal hormone of the renin angiotensin system, is actively generated in the pancreas and has been suggested as a key mediator of PDA cell survival. Fatty acid synthase (FAS) is a key enzyme involved in synthesis of fatty acids and its high levels have been correlated with poor prognosis in many cancers. In this study, we investigated the potential molecular basis for the role of AngII in pancreatic carcinogenesis through studying its effect on FAS. AngII significantly increased the expression of FAS mRNA and protein in Panc-1 and PK9 PDA cells lines and induced FAS promoter activity. AngII-FAS mRNA induction was inhibited by an AngII type 1 receptor (AT1R) antagonist, losartan, and to a lesser extent by an AT2R antagonist. AngII activated the phosphorylation of ERK1/2, but not p38 or c-Jun NH2-terminal MAP kinases. Inhibition of ERK1/2 activation reduced the AngII-induced FAS synthesis. AngII activated the phosphorylation of AKT. Inhibition of AKT activation prevented the AngII-mediated increase of FAS. In human premalignant (n=6) and invasive PDA lesions (n=25), high expression levels of FAS correlated well with tumor stage and invasion status, and with high expression levels of angiotensin converting enzyme (ACE). Immunohistochemical staining of PDA serial sections show co localization of ACE with FAS in the malignant ducts and stromal cells. Oral administration of losartan significantly (p< 0.05) decreased the growth of PANC-1 and PK-9 cells xenografted on the flank of nude mice and significantly (p<0.05) reduced the expression of FAS mRNA and protein in the xenografts. Our data suggest a positive autocrine/paracrine action for the local pancreatic AngII generating system during pancreatic carcinogenesis, and provide the first insight into an AngII-initiated signal transduction pathway that regulates fatty acid metabolism and modulate lipogenesis in PDA. These results raise the possibility that AngII blockade therapies could be potential candidates in novel treatment strategies of PDA. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 51.