Induction of 3-hydroxy-3-methylglutaryl-CoA reductase mediates statin resistance in breast cancer cells

• DOI: 10.1038/s41419-019-1322-x
• Publication Date: 2019-01-28T11:02:48Z
• Authors: Andy Göbel; Dorit Breining; Martina Rauner; Lorenz C. Hofbauer; Tilman D. Rachner
• Keywords: Hydroxymethylglutaryl-CoA Reductase Inhibitors

Abstract The mevalonate pathway has emerged as a promising target for several solid tumors. Statins are inhibitors of the 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), rate-limiting enzyme this pathway, and commonly used to treat patients with hypercholesterolemia. Pleiotropic antitumor mechanisms statins have been demonstrated human cancer types. However, cells differ in their individual statin sensitivity some cell lines shown relative resistance. In study we demonstrate, that breast MDA-MB-231, MDA-MB-468, MCF-7, T47D differentially affected by statins. Whereas vitality MDA-MB-231 MDA-MB-468 was reduced up 60% using atorvastatin, simvastatin, or rosuvastatin ( p < 0.001), only marginal effects were seen MCF-7 following exposure Statin treatment led an upregulation HMGCR mRNA protein expression sixfolds statin-resistant but no alterations observed statin-sensitive cells. knockdown prior sensitized resistant lines, reflected 70% reduction vitality, increased apoptotic DNA fragmentation (sixfold) accumulation apoptosis marker cleaved poly-ADP ribose polymerase. induced cleavage sterol-regulatory element-binding (SREBP)-2, transcriptional activator HMGCR, inhibition SREBP-2 activation co-administration dipyridamole (loss 80%; 0.001). Furthermore, assessment clone, generated long-term sublethal exposure, revealed significant induction 12-folds Knockdown restored back levels parental conclusion, these results indicate resistance against statins, which is part due HMGCR.