Oxysterols synergize with statins by inhibiting SREBP-2 in ovarian cancer cells

Abstract

Objective Determine mechanisms responsible for enhanced statin efficacy in a novel statin combination we name STOX (STatin–OXysterol). Methods Ovarian cancer cell lines were treated with combinations of statins and oxysterols. Cell viability was determined by a modified MTT assay. Apoptosis was evaluated by immunoblotting of PARP and DAPI-mediated visualization of apoptotic nuclei. STOX effects on the expression of genes of the mevalonate pathway were assessed by real-time qPCR and immunoblotting. siRNA-mediated gene silencing was used to test the involvement of oxysterol-mediated repression of SREBP-2 in STOX synergy. The impact of statin-mediated inhibition of protein prenylation and on cholesterol homeostasis was evaluated. Results Oxysterols dramatically enhance cytotoxicity of statins in ovarian cancer cells through increased apoptosis. Decreased expression of SREBP-2 down-regulates the mevalonate pathway and prevents the active statin-induced sterol feedback, enhancing statin toxicity. Comparison of two ovarian cancer cell lines reveals two distinct mechanisms of statin induced toxicity, namely, dependence on protein geranylgeranylation and/ or perturbation of cellular cholesterol levels. Conclusions We provide evidence of statins' mechanisms of cytotoxicity in different ovarian cancer cells and discovered a new approach to significantly enhance the anti-tumor activity of statins. These observations provide a potential new path to improve statins as a treatment against ovarian cancer with obtainable dosages.

Role of the Sterol Regulatory Element Binding Protein Pathway in Tumorigenesis

“…Hence, inhibition of HMGCR and SREBPs would increase responsiveness to drugs (144). The same drug resistance mechanism related to SREBPs and lipid metabolism was also found in breast tumors, multiple myeloma, glioblastoma, lung tumors, and liver tumors (22,58,77,(145)(146)(147), as well as antitumor drugs, including cisplatin (148), rapamycin, epidermal growth factor receptor-targeted inhibitors and docetaxel (57,147,149). Natural drugs combined with traditional anti-tumor drugs to increase the sensitivity of cells to treatment are very promising.…”

Role of lipids in the metabolism and activation of immune cells

“…Knockdown of CYP7B1 in an apolipoprotein E (apoE) atherosclerotic mouse model leads to elevated inflammation and accelerated atherosclerotic lesion formation [33]. Similarly, in vitro studies have shown that direct treatment of macrophages with 27HC increases IL-6, TNF-α and IL-1β expression [34–36]. Mechanistically, 27HC drives the M1 phenotype in macrophages through the estrogen receptor alpha [30].…”

“…Desmosterol is the most prevalent sterol in atherosclerotic plaques and is a ligand for both LXR and SREBP [31–34]. When macrophages have elevated intracellular cholesterol, desmosterol metabolism is inhibited, leading to elevated desmesterol.…”

Anti-tumor effects of mevalonate pathway inhibition in ovarian cancer

“…We and others have demonstrated a restorative feedback loop by induction of the statin targeting enzyme, the HMGCR, as a mediator of statin resistance in human breast and prostate cancer as well as multiple myeloma cells [ 52 , 79 , 80 ]. Similar mechanisms might occur in ovarian cancer cells, especially as cisplatin and simvastatin induce a strong accumulation of HMGCR in ovarian cancer cells [ 81 , 82 ]. In times of personalized medicine, it would be greatly relevant to identify patients with those molecular subtypes, that would mostly benefit from a statin or N-BP therapy, individually or in combination with chemotherapy, as well as to define the optimal therapeutic window.…”