Chemotherapy resistance due to epithelial-to-mesenchymal transition is caused by abnormal lipid metabolic balance

Area of Science:

• Oncology
• Molecular Biology
• Cancer Research

Background:

• Invasive cancer is characterized by the loss of epithelial traits, often driven by epithelial-mesenchymal transition (EMT).
• EMT is linked to chemoresistance, but the underlying molecular mechanisms are not fully understood.
• Transcription factors like Snail play a key role in EMT.

Purpose of the Study:

• To elucidate the molecular mechanisms by which Snail-mediated EMT confers chemoresistance.
• To investigate the role of lipid metabolism in Snail-induced chemoresistance.
• To explore potential lipid-targeting therapeutic strategies for invasive cancers.

Main Methods:

• Analysis of Snail expression in cancer cells.
• Measurement of cholesterol and sphingomyelin levels.
• Assessment of ABCA1 (ATP-binding cassette transporter A1) expression.
• Enzyme activity assays for sphingomyelin biosynthesis.
• Inhibition of cholesterol esterification in a xenograft model.

Main Results:

• Snail expression upregulates the cholesterol efflux pump ABCA1.
• Snail represses enzymes involved in sphingomyelin biosynthesis, leading to an imbalance of free cholesterol and sphingomyelin.
• This lipid imbalance contributes to chemoresistance.
• Inhibiting cholesterol esterification selectively suppressed the growth of Snail-positive kidney cancer xenografts.

Conclusions:

• Snail-driven chemoresistance involves the dysregulation of cellular lipid metabolism, specifically the cholesterol-sphingomyelin balance.
• ABCA1 upregulation and sphingomyelin biosynthesis repression are key mechanisms.
• Targeting cholesterol esterification presents a promising therapeutic avenue for invasive cancers expressing Snail.