4-cholesten-3-one decreases breast cancer cell viability and alters membrane raft-localized EGFR expression by reducing lipogenesis and enhancing LXR-dependent cholesterol transporters

Abstract

Background The alteration of lipid metabolism in cancer cells is recognized as one of the most important metabolic hallmarks of cancer. Membrane rafts defined as plasma membrane microdomains enriched in cholesterol and sphingolipids serve as platforms for signaling regulation in cancer. The main purpose of this study was to evaluate the effect of the cholesterol metabolite, 4-cholesten-3-one, on lipid metabolism and membrane raft integrity in two breast cancer cell lines, MCF-7 and MDA-MB-231. Its ability to reduce cell viability and migration has also been investigated. Methods RT-qPCR was performed to evaluate the expression of enzymes involved in lipogenesis and cholesterol synthesis, and ABCG1 and ABCA1 transporters involved in cholesterol efflux. Its effect on cell viability and migration was studied using the MTT assay, the wound healing assay and the Transwell migration assay, respectively. The effect of 4-cholesten-3-one on membrane rafts integrity was investigated by studying the protein expression of flotillin-2, a membrane raft marker, and raft-enriched EGFR by western blot. Results Interestingly, we found that 4-cholesten-3-one treatment decreased mRNA expression of different enzymes including ACC1, FASN, SCD1 and HMGCR. We further demonstrated that 4-cholesten-3-one increased the expression of ABCG1 and ABCA1. We also found that 4-cholesten-3-one decreased the viability of MCF-7 and MDA-MB-231 cells. This effect was neutralized after treatment with LXR inverse agonist or after LXRβ knockdown by siRNA. As a result, we also demonstrated that 4-cholesten-3-one disrupts membrane rafts and cell migration capacity. Conclusion Our results show that 4-cholesten-3-one exerts promising antitumor activity by altering LXR-dependent lipid metabolism in breast cancer cells without increasing lipogenesis.

Modulation of LXR signaling altered the dynamic activity of human colon adenocarcinoma cancer stem cells in vitro

“…The activation of LXR seems to decrease the CSCs invasion and migration. These results could be related to the role of CHOL is an important component of membrane lipid rafts containing the signaling molecules precipitating in cell migration [ 16 , 32 , 33 ]. Moreover, ABCA1 modulates CHOL distribution in the membrane which affected the pathways promoting cell migration [ 9 ].…”

Natural Products Targeting Liver X Receptors or Farnesoid X Receptor

“…To confirm this effect, LXRs inverse agonist and LXRβ knockdown were employed, which resulted in the neutralization. Further study showed that 78 decreased the viability of two breast cancer cell lines, namely MCF-7 and MDA-MB-231, exerting promising antibreast cancer activity by altering LXRs-dependent lipid metabolism in breast cancer cells without increasing lipogenesis ( Elia et al, 2019 ). Gorgostane-3β,9α,5α,6β,11α-tetrol (79) and gorgost-5-ene-3β,9α,11α-triol (80) isolated from the Plexaura species possessed a better affinity with LXRα than LXRβ with EC 50 values of 0.45 and 0.05 μM ( Jayasuriya et al, 2005 ).…”

Isolation of the Cholesterol-Assimilating Strain Pediococcus acidilactici LRCC5307 and Production of Low-Cholesterol Butter

“…Cholesterol oxidase is a FAD-dependent (flavin adenine dinucleotide) enzyme that catalyzes the oxidation and isomerization of sterols to sterones, typically cholesterol (5-cholesten-3- β -ol) to 4-cholesten-3-one (cholestenone) ( Lashgarian et al, 2016 ; Pan et al, 2011 ; Sakodinskaya and Ryabov, 2000 ). Studies have shown that cholestenone, which is produced as a metabolite, is safe and can be used to control obesity, treat liver disease, and prevent keratinization of the skin ( Elia et al, 2019 ). Wali et al (2019) isolated Bacillus pumilus W1 and Serratia marcescens W8 from soil contaminated with oil and reported that these strains degrade cholesterol and produce red colonies in M9 medium containing 0.1% cholesterol as the only carbon source.…”