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

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

The mevalonate precursor enzyme HMGCS1 is a novel marker and key mediator of cancer stem cell enrichment in luminal and basal models of breast cancer

“…A statin-dependent upregulation of HMGCS1, together with other genes belonging to the mevalonate pathway, has also been described in multiple myeloma cells [44]. This feedback mechanism has been associated with statin-insensitivity upon statin exposure in leukemic cells [44], and recently also in breast cancer cells [45]. In our study, Simvastatin treatment had no or mild effect in the viability of the CSC-enriched cultures of the three assayed cell lines.…”

Statin-boosted cellular uptake of penetratin due to reduced membrane dipole potential

“…Although reduction of the dipole potential in both MDA-MD-231 and SKBR-3 cells resulted in enhanced penetratin accumulation in the cytosol after phloretin treatment, the latter cell line exhibited lower sensitivity to atorvastatin. Sensitivity to statins correlates inversely with HMG-CoA reductase activity (56,57). While the expression of this enzyme is higher by 20-30% in SKBR-3 cells according to a publication (57) Completion of deprotection was assessed by Kaiser test.…”

Cholesterol and Mevalonate: Two Metabolites Involved in Breast Cancer Progression and Drug Resistance through the ERRα Pathway

“…Mevalonate is a pivotal intermediate for cholesterol synthesis, as well as a precursor of ubiquinone, which is a main character in mitochondrial bioenergetics [11,12]. It is well-accepted that the mevalonate pathway drives malignant transformation [7,13,14] and since statins are well-established drugs used to lower serum cholesterol in patients, inhibiting the HMGCR [15], several studies have been performed to show that statins exert antitumor effects in human malignancies, including breast cancer [16,17]. However, the role of statins is debatable; indeed, other studies have failed to show any meaningful anti-tumor effect [18].…”