Insensitivity to atorvastatin is associated with increased accumulation of intracellular lipid droplets and fatty acid metabolism in breast cancer cells

Abstract

Apart from the relevant lipid-lowering effects, statins have demonstrated significant, although heterogeneous, anti-tumor activities in preventing breast cancer (BC) progression. To characterize the critical pathways behind the diverse responses to therapy, we investigated statin-induced changes in regulation of lipid metabolism and abundance of neutral lipid-containing cytoplasmic lipid droplets (LDs) in BC cells displaying different sensitivity to atorvastatin. Following atorvastatin treatment, accumulated LD levels inversely mirrored the marginal anti-proliferative effects in a dose and time-dependent manner in the less-sensitive BC cells. Transcriptional profiling excluded dysregulation of lipid uptake and efflux as specific mechanisms associated with differences in LD accumulation and anti-proliferative effects of atorvastatin. Notably, significant upregulation of genes involved in unsaturated fatty acid metabolism [stearoyl-CoA desaturase (SCD)] and cholesterol biosynthesis [3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR)], were associated with atorvastatin insensitivity. Taken together, the increased ability to store neutral lipids in LDs as consequence of atorvastatin treatment likely confers a proliferative advantage to BC cells and may serve as potential biomarker of statin resistance in BC. Contributions of cholesterol biosynthesis and unsaturated fatty acid metabolism to LD formation should be thoroughly explored for better understanding of the molecular mechanisms underlying statin-induced effects against BC progression.

Increased Cholesterol Biosynthesis Is a Key Characteristic of Breast Cancer Stem Cells Influencing Patient Outcome

“…FTIs have been shown to improve breast cancer prognosis in a phase II clinical trial (Johnston et al, 2003), especially for TNBC (Brewer et al, 2013), and statins have been shown in various breast cancer cell lines to increase apoptosis and decrease the metastatic dissemination of tumors (Van Wyhe et al, 2017). Not all breast cancer cell lines are sensitive to statins, and a very recent study suggests that de novo cholesterol biosynthesis is not required for statin-resistant cell proliferation since these cells increase the exogenous uptake of cholesterol and lipids by increasing the transcription of, for example, 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) (Lettiero et al, 2018). Simvastatin is being evaluated in a phase II clinical trial for metastatic HER2 + breast cancer (Rimawi, 2019).…”

The effect of statin treatment on intratumoral cholesterol levels and LDL receptor expression: a window-of-opportunity breast cancer trial

“…From an opposite perspective, these results indicate that the upregulation of LDLR might avert the anti-tumoral effects of statins and raises the question if statin treatment should be avoided in patients with the most apparent LDLR upregulation, or be combined with inhibition of LDLR, a target with emerging therapeutic options [ 69 – 71 ]. Also, preclinical studies have shown a difference in sensitivity to statins between different breast cancer cell lines, where ER-positive cell lines were found to be more insensitive to statins than ER negative [ 72 , 73 ]. The relative insensitivity was found to be associated with increased accumulation of intracellular lipid droplets and fatty acid metabolism [ 73 ] and the upregulation of HMGCR and LDLR mRNA levels, which is thought to be mediated by a dysregulation of the feedback response via the SREBP-2/HMGCR/LDLR axis that counteracts the inhibition of the mevalonate pathway [ 72 ].…”

Simvastatin is a potential candidate drug in ovarian clear cell carcinomas

“…Cells were plated at 5,000 cells/well in a 96-MicroWell Nunclon plate (VWR) and left for 24 hours after which they were then treated with drugs for 72 hours, with DMSO as the control. Proliferation was evaluated using the sulforhodamine-B assay as described previously [51]. Concentration response curves and IC50 concentrations for single agent regimens and combination treatments were calculated and analyzed using the drc package (Version 3.0-1) [52] in R (Version 3.3.3) [53].…”