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

Abstract

BACKGROUND:

Statin 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.

METHODS:

These 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.

RESULTS:

All 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.

CONCLUSIONS:

Our 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.

• Authors: Helena Gbelcová, Silvie Rimpelová, Zdeněk Knejzlík, Jana Šáchová, Michal Kolář, Hynek Strnad, Vanda Repiská, Walter Cosimo D'Acunto, Tomáš Ruml, Libor Vítek
• Journal: Lipids in health and disease (Lipids Health Dis) Vol. 16 Issue 1 Pg. 250 (Dec 20 2017) ISSN: 1476-511X [Electronic] England
• PMID: 29262834 (Publication Type: Journal Article)

Chemical References

• Anticholesteremic Agents
• Fatty Acids, Monounsaturated
• Indoles
• KRAS protein, human
• Polyisoprenyl Phosphates
• Recombinant Fusion Proteins
• Sesquiterpenes
• Green Fluorescent Proteins
• Fluvastatin
• farnesyl pyrophosphate
• Lovastatin
• Atorvastatin
• Simvastatin
• Proto-Oncogene Proteins p21(ras)
• geranylgeranyl pyrophosphate
• Mevalonic Acid

Topics

• Anticholesteremic Agents (pharmacology)
• Atorvastatin (pharmacology)
• Cell Line, Tumor
• Fatty Acids, Monounsaturated (pharmacology)
• Fluvastatin
• Gene Expression Profiling
• Gene Expression Regulation
• Green Fluorescent Proteins (genetics, metabolism)
• Humans
• Indoles (pharmacology)
• Insulin-Secreting Cells (drug effects, metabolism, pathology)
• Lovastatin (pharmacology)
• Mevalonic Acid (analogs & derivatives, pharmacology)
• Microarray Analysis
• Mutation
• Polyisoprenyl Phosphates (pharmacology)
• Protein Prenylation
• Protein Transport (drug effects)
• Proto-Oncogene Proteins p21(ras) (genetics, metabolism)
• Recombinant Fusion Proteins (genetics, metabolism)
• Sesquiterpenes (pharmacology)
• Signal Transduction
• Simvastatin (pharmacology)