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

Abstract

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.Electronic supplementary materialThe online version of this article (10.1186/s12944-017-0641-0) contains supplementary material, which is available to authorized users.

Cholesterol metabolism drives regulatory B cell IL-10 through provision of geranylgeranyl pyrophosphate

“…This preprogramming requires the generation of GGPP prior to cellular stimulation (rather than upon or as a direct consequence of stimulation), that has the effect of fine-tuning signaling cascades. This notion of preprogramming is consistent with data showing the GGPP-dependent constitutive localization of Ras family proteins at the cell membrane and endosomes, and that blockade of cholesterol metabolism retains Ras in the cytoplasm 38 , 39 . In other words, the state of signaling intermediates is preset by the state of cholesterol metabolism of the quiescent cell at any given point.…”

Cholesterol metabolism drives regulatory B cell function

“…This pre-direct consequence of stimulation), that has the effect of fine-tuning signaling cascades. This notion of pre-programming is consistent with data showing the GGPP-dependent constitutive localization of Ras family proteins at the cell membrane and endosomes, and that blockade of cholesterol metabolism retains Ras in the cytoplasm 36,37 . In other words, the state of signaling intermediates is 270 preset by the state of cholesterol metabolism of the quiescent cell at any given point.…”

Lipid rafts as signaling hubs in cancer cell survival/death and invasion: implications in tumor progression and therapy

“…Overall, the epidemiological results have been mixed and largely dependent on both the type of tumor in question and the particular statin that was used (56). Statins inhibit the rate-limiting enzyme that converts HMG-CoA into mevalonate, which in turn serves as a precursor for the synthesis of a number of downstream products, including cholesterol, ubiquinone, dolichol, and the isoprenoids geranylgeranyl pyrophosphate and farnesyl pyrophosphate that bind to several small GTP-binding proteins, such as RAS and RHO, facilitating protein translocation from the cytosol to the plasma membrane (57,58). Thus, the inhibition of the mevalonate pathway by statins provokes pleiotropic antitumor effects, although statin sensitivity of cancer cell lines varies, and ambiguous results have been obtained in clinical trials (59).…”