Cancer medicine · 2026
Cholesterol-Lowering Treatment Blocks Epithelial-Mesenchymal Transition (EMT) Associated Invasiveness and Drug Resistance in Breast and Colorectal Adenocarcinoma Models.
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Perumal Shanen, Abdulla Naaziyah, Aronson Ruth, Kaur Mandeep
Аннотация
BACKGROUND: Epithelial-mesenchymal transition (EMT) is a cellular process involved in the invasion and metastasis of cancer cells. Deregulated cellular cholesterol is associated with treatment resistance and metastatic potential in cancer cells; however, the link between EMT and cholesterol is unclear.
METHODS: We tested the effect of cholesterol-lowering on EMT using three cell line models and three EMT inducers. EMT was induced in NMuMG, MCF-7 and HT-29 cells to assess the effect of cholesterol-modulatory compounds, MβCD, HPβCD and simvastatin. Free cholesterol, lipid droplets and lipid rafts in cellular membranes were evaluated using immunofluorescence microscopy. Expression of EMT-associated genes was assessed using immunofluorescent staining, RT-qPCR and Western blotting.
RESULTS: Following cholesterol depletion (free cholesterol, lipid rafts and lipid droplets) with HPβCD, RT-qPCR showed an increase in CDH1 expression (log2 fold change [log2FC] = 2.03; p < 0.001), and a decrease in Vim (log2FC = -1.01; p < 0.05) in NMuMG cells post EMT. Expression of cholesterol biosynthesis gene HMGCR (log2FC = -1.72; p < 0.01), and efflux genes ABCA1 (log2FC = -1.74; p < 0.01) and ABCG1 (log2FC = -4.81; p < 0.001) were reduced. A 68.4% (p < 0.001) reduction in relative invasion in NMuMG cells and a 41.3% (p < 0.01) reduction in multidrug resistance measurements in MCF-7 cells were observed post-EMT after HPβCD treatment.
CONCLUSION: Cholesterol depletion reversed EMT-associated expression patterns in all three cell models. Results from this study support cholesterol depletion as a potential therapeutic intervention for mitigating metastatic cancer progression.
METHODS: We tested the effect of cholesterol-lowering on EMT using three cell line models and three EMT inducers. EMT was induced in NMuMG, MCF-7 and HT-29 cells to assess the effect of cholesterol-modulatory compounds, MβCD, HPβCD and simvastatin. Free cholesterol, lipid droplets and lipid rafts in cellular membranes were evaluated using immunofluorescence microscopy. Expression of EMT-associated genes was assessed using immunofluorescent staining, RT-qPCR and Western blotting.
RESULTS: Following cholesterol depletion (free cholesterol, lipid rafts and lipid droplets) with HPβCD, RT-qPCR showed an increase in CDH1 expression (log2 fold change [log2FC] = 2.03; p < 0.001), and a decrease in Vim (log2FC = -1.01; p < 0.05) in NMuMG cells post EMT. Expression of cholesterol biosynthesis gene HMGCR (log2FC = -1.72; p < 0.01), and efflux genes ABCA1 (log2FC = -1.74; p < 0.01) and ABCG1 (log2FC = -4.81; p < 0.001) were reduced. A 68.4% (p < 0.001) reduction in relative invasion in NMuMG cells and a 41.3% (p < 0.01) reduction in multidrug resistance measurements in MCF-7 cells were observed post-EMT after HPβCD treatment.
CONCLUSION: Cholesterol depletion reversed EMT-associated expression patterns in all three cell models. Results from this study support cholesterol depletion as a potential therapeutic intervention for mitigating metastatic cancer progression.