Simvastatin Reduces Cancerogenic Potential of Renal Cancer Cells via Geranylgeranyl Pyrophosphate and Mevalonate Pathway

Abstract

Simvastatin is a cholesterol-lowering drug, inhibiting 3-hydroxy-3-methylglutaryl-coenzyme CoA (HMG-CoA) reductase. Previous studies have indicated the anticancerous effects of simvastatin. Here, we evaluated the anticancerous potential of simvastatin in renal cell carcinoma (RCC) cell lines. RCC occurs with an incidence of 2-3% of all cancer entities with high chemoresistance rate. Therefore, the understanding of underlying mechanisms for RCC activity and the development of alternative therapies are essential. Human RCC cell lines Caki-1 and KTC-26 were treated with simvastatin (16 or 33 µM) for 48 or 72 h. The effects of the downstream substrates mevalonate (MA), farnesyl pyrophosphate (FPP), and geranylgeranyl pyrophosphate (GGPP) were evaluated using add-back experiments. Cell growth was assessed using MTT assay. Apoptosis and cell cycle were analyzed by flow cytometry. Apoptosis-involved proteins were evaluated by Western blot. Simvastatin caused dose- and time-dependent inhibition of RCC cell growth by cell cycle arrest and apoptosis induction. Substitution of MA or GGPP abolished these effects to a large extent. These findings suggest that the antiproliferative effects of simvastatin are not only mediated through cholesterol deprivation but also by prenylation-associated mechanisms, thereby providing new insights into tumor-suppressive ability of simvastatin and into novel additive treatment options in the management of RCC.

Lipid-Producing Ciliochoroidal Melanoma with Expression of HMG-CoA Reductase

“…Enhanced cholesterol biosynthesis has been shown to play a role in prostate cancer development (reviewed by Hager et al [19]), for example, and blocking the mevalonate pathway may have antineoplastic potential [20][21][22]. While epidemiological evidence on statin use and cancer survival are as yet inconclusive [23,24], some preclinical trials of mevalonate pathway inhibitors have shown promising effects as primary or adjuvant therapy in several malignancies, including ovarian cancer [25,26], breast cancer [22,27], and renal cell carcinoma [28]. Despite these promising developments, clinical trials have not yet demonstrated consistently significant benefits for patients treated with mevalonate pathway inhibitors [29].…”

The Potential of Isoprenoids in Adjuvant Cancer Therapy to Reduce Adverse Effects of Statins

“…Furthermore, statins inhibit tumor cell invasion, migration, and metastasis by attenuating the geranylgeranylation and activation of Rho oncoproteins (Al-Haidari et al, 2014; Kato et al, 2018). Conversely, mevalonate and GGPP abolished statin-induced effects on p-AKT, p-ERK, cell cycle arrest, and apoptosis in several tumors including human HL-60 leukemia cells (Chen et al, 2015), ovarian cancer cells (de Wolf et al, 2017), MiaPaCa-2 pancreatic cancer cells (Gbelcova et al, 2017), Caki-1 and KTC-26 renal carcinoma cells (Woschek et al, 2016), and malignant anaplastic thyroid cancer (Chen et al, 2017). By blocking the synthesis of mevalonate-derived metabolites that hinder the ubiquitination and degradation of mutant p53 protein, statins also suppress the growth of mutant p53-expressing cancer cells (Freed-Pastor et al, 2012; Freed-Pastor and Prives, 2016; Parrales et al, 2016).…”

Targeting energy metabolism to eliminate cancer cells

“… 30 Simvastatin exerted an antiproliferative effect in renal cancer cells through cholesterol deprivation and prenylation-associated mechanisms. 31 …”