UGT8 mediated sulfatide synthesis modulates BAX localization and dictates apoptosis sensitivity of colorectal cancer

Area of Science:

• Cancer Biology
• Lipid Metabolism
• Apoptosis Regulation

Background:

• Cancer cells exhibit elevated de novo lipid synthesis, a potential therapeutic target.
• The precise role of altered lipid metabolism in apoptosis regulation remains unclear.
• Understanding lipid metabolism's impact on cancer cell death is crucial for novel therapies.

Purpose of the Study:

• To investigate the link between lipid metabolism and apoptosis in colorectal cancer.
• To identify novel therapeutic targets modulating lipid synthesis for cancer treatment.
• To elucidate the mechanism by which lipid alterations influence cancer cell death pathways.

Main Methods:

• Thermal proteome profiling to identify drug targets.
• Lipidomic analysis to quantify sulfatide levels.
• Assessment of mitochondrial function and apoptosis markers (e.g., BAX localization).

Main Results:

• Manidipine-2HCl identified as a UGT8 inhibitor, significantly reducing sulfatides in colorectal cancer cells.
• Sulfatide reduction induced mitochondrial swelling and potentiated apoptosis.
• Manidipine-2HCl enhanced BCL-XL targeting BH3 mimetic efficacy, dependent on sulfatide levels and BAX localization.

Conclusions:

• UGT8-mediated sulfatide synthesis is critical for maintaining mitochondrial homeostasis.
• Targeting sulfatide synthesis with Manidipine-2HCl sensitizes colorectal cancer cells to apoptosis.
• Sulfatide levels dictate mitochondrial BAX localization and sensitivity to apoptosis-inducing drugs.