Isoprenoids responsible for protein prenylation modulate the biological effects of statins on pancreatic cancer cells

Lipids in Health and Disease

Research

Silvie Rimpelová¹  Walter Cosimo D’Acunto¹  Zdeněk Knejzlík¹  Tomáš Ruml¹  Libor Vítek²  Vanda Repiská³  Helena Gbelcová⁴  Hynek Strnad⁵  Jana Šáchová⁵  Michal Kolář⁵ 

[1] Department of Biochemistry and Microbiology, University of Chemistry and Technology, Prague, Czech Republic;Institute of Medical Biochemistry and Laboratory Diagnostics, and 4th Department of Internal Medicine, 1st Faculty of Medicine, Charles University, Prague, Czech Republic;Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Medicine, Comenius University, Bratislava, Slovakia;Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Medicine, Comenius University, Bratislava, Slovakia;Department of Biochemistry and Microbiology, University of Chemistry and Technology, Prague, Czech Republic;Laboratory of Genomics and Bioinformatics, Institute of Molecular Genetics of the Academy of Sciences of the Czech Republic, Prague, Czech Republic;

关键词: Farnesyl pyrophosphate;    Gene expression;    Geranylgeranyl pyrophosphate;    HMG-CoA reductase inhibitors;    Isoprenoids;    K-Ras;    Mevalonate;    Pancreatic cancer;    Prenylation;    Statins;   

DOI  :  10.1186/s12944-017-0641-0

 received in 2017-07-14, accepted in 2017-12-05,  发布年份 2017

来源: Springer

【 摘 要 】

BackgroundStatin treatment of hypercholesterolemia is accompanied also with depletion of the mevalonate intermediates, including farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP) necessary for proper function of small GTPases. These include Ras proteins, prevalently mutated in pancreatic cancer. In our study, we evaluated the effect of three key intermediates of the mevalonate pathway on GFP-K-Ras protein localization and the gene expression profile in pancreatic cancer cells after exposure to individual statins.MethodsThese effects were tested on MiaPaCa-2 human pancreatic cancer cells carrying a K-Ras activating mutation (G12C) after exposure to individual statins (20 μM). The effect of statins (atorvastatin, lovastatin, simvastatin, fluvastatin, cerivastatin, rosuvastatin, and pitavastatin) and mevalonate intermediates on GFP-K-Ras protein translocation was analyzed using fluorescence microscopy. The changes in gene expression induced in MiaPaCa-2 cells treated with simvastatin, FPP, GGPP, and their combinations with simvastatin were examined by whole genome DNA microarray analysis.ResultsAll tested statins efficiently inhibited K-Ras protein trafficking from cytoplasm to the cell membrane of the MiaPaCa-2 cells. The inhibitory effect of statins on GFP-K-Ras protein trafficking was partially prevented by addition of any of the mevalonate pathway’s intermediates tested. Expressions of genes involved in metabolic and signaling pathways modulated by simvastatin treatment was normalized by the concurrent addition of FPP or GGPP. K-Ras protein trafficking within the pancreatic cancer cells is effectively inhibited by the majority of statins; the inhibition is eliminated by isoprenoid intermediates of the mevalonate pathway.ConclusionsOur data indicate that the anticancer effects of statins observed in numerous studies to a large extent are mediated through isoprenoid intermediates of the mevalonate pathway, as they influence expression of genes involved in multiple intracellular pathways.

【 授权许可】

CC BY   
© The Author(s). 2017