title: 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.
authors.affiliation: a Department of Trauma , Hand and Reconstructive Surgery, University Hospital Frankfurt, Goethe University , Frankfurt am Main , Germany.
authors.forename: Mathias
authors.initials: M
authors.lastname: Woschek
authors.affiliation: a Department of Trauma , Hand and Reconstructive Surgery, University Hospital Frankfurt, Goethe University , Frankfurt am Main , Germany.
authors.forename: Niels
authors.initials: N
authors.lastname: Kneip
authors.affiliation: a Department of Trauma , Hand and Reconstructive Surgery, University Hospital Frankfurt, Goethe University , Frankfurt am Main , Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Jurida
authors.affiliation: a Department of Trauma , Hand and Reconstructive Surgery, University Hospital Frankfurt, Goethe University , Frankfurt am Main , Germany.
authors.forename: Ingo
authors.initials: I
authors.lastname: Marzi
authors.affiliation: a Department of Trauma , Hand and Reconstructive Surgery, University Hospital Frankfurt, Goethe University , Frankfurt am Main , Germany.
authors.forename: Borna
authors.initials: B
authors.lastname: Relja
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D053858:Metabolic Networks and Pathways / Q000187:drug effects; D008798:Mevalonic Acid / Q000378:metabolism* / Q000494:pharmacology; D011106:Polyisoprenyl Phosphates / Q000378:metabolism* / Q000494:pharmacology; D012717:Sesquiterpenes / Q000378:metabolism / Q000494:pharmacology; D019821:Simvastatin / Q000008:administration & dosage / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D051017:Apoptosis Regulatory Proteins; D011106:Polyisoprenyl Phosphates; D012717:Sesquiterpenes; C004808:farnesyl pyrophosphate; D019821:Simvastatin; C002963:geranylgeranyl pyrophosphate; D008798:Mevalonic Acid