Simvastatin inhibits sonic hedgehog signaling and stemness features of pancreatic cancer. (10th July 2018)

• Record Type: Journal Article
• Authors: Yin, Yefeng; Liu, Li; Zhao, Zhefu; Yin, Libo; Bauer, Nathalie; Nwaeburu, Clifford C.; Gladkich, Jury; Gross, Wolfgang; Hackert, Thilo; Sticht, Carsten; Gretz, Norbert; Strobel, Oliver; Herr, Ingrid
• Is Part Of: Cancer letters. Volume 426(2018)
• Page Start: 14
• Page End: 24
• Publication Date: 2018-07-10
• Subjects: Pancreatic cancer -- Simvastatin -- Cancer stem cells -- Sonic Hedgehog; BMP4 Bone morphogenetic protein 4 -- ClSCs Cancer stem cells -- GEM Gemcitabine -- Shh sonic Hedgehog -- SIM Simvastatin -- PDA Pancreatic ductal adenocarcinoma; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2018.04.001
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: Pancreatic ductal adenocarcinoma (PDA) has poor therapeutic options. Recent patient studies indicate that cholesterol-lowering statins have anti-tumor capacities. We examined several established and primary PDA and normal cell lines as well as PDA patient tissues (n = 68). We found that simvastatin inhibited viability, stemness, tumor growth and metastasis and that it enhanced the efficacy of gemcitabine. These changes were associated with modulation of Shh-related gene expression. Overexpression of Shh prevented the anti-cancer effect of simvastatin, and inhibition of Shh mimicked the simvastatin effect. In PDA tissues, expression levels of Shh, downstream mediators of Shh and progression markers, namely, cMet, CxCR4 and Vimentin, were lower when patients were prescribed statin medication prior to surgery. These results suggested that statins are cost effective and well-tolerated drugs for prevention and co-treatment of PDA. Highlights: We found that simvastatin inhibits stemness and tumor growth in pancreatic cancer and increases drug response. This was due to simvastatin-mediated inhibition of sonic hedgehog and its downstream mediators Gli1 and Smoothened. This expression pattern was confirmed in tissue of patients, who had taken statins or not. These results suggest statins for prevention and co-treatment of PDA and provide new mechanistic data.