Targeting Acid Ceramidase to Improve the Radiosensitivity of Rectal Cancer

Area of Science:

• Oncology
• Molecular Biology
• Radiotherapy

Background:

• High acid ceramidase (AC) expression correlates with poor response to neoadjuvant treatment in locally advanced rectal cancer.
• Understanding AC's role in radioresistance is crucial for improving treatment outcomes.

Purpose of the Study:

• To investigate the radiosensitizing effect of manipulating acid ceramidase (AC) expression and activity.
• To elucidate the molecular mechanisms underlying AC's influence on colorectal cancer cell radiosensitivity.

Main Methods:

• Utilized siRNA, plasmid overexpression, and CRISPR gene editing to modulate AC levels in colorectal cancer cell lines (HT29, HCT116, LIM1215).
• Employed pharmacological inhibitors (carmofur, LCL521) to block AC activity.
• Assessed radiosensitivity using clonogenic assays and patient-derived organoid models.
• Investigated downstream effects including PARP-1 cleavage and apoptosis via Western blotting and p53 pathway analysis.

Main Results:

• AC knockdown and knockout significantly increased radiosensitivity, while AC overexpression led to radioresistance.
• Pharmacological inhibition of AC with carmofur and LCL521 enhanced radiosensitivity across tested cell lines.
• AC inhibition promoted poly-ADP ribose polymerase-1 (PARP-1) cleavage and apoptosis post-irradiation in a p53-dependent manner.
• Patient-derived organoids with lower AC expression exhibited greater radiosensitivity.

Conclusions:

• Acid ceramidase (AC) expression levels directly modulate colorectal cancer cell response to radiation.
• Inhibiting AC activity significantly enhances cellular radiosensitivity, primarily by increasing apoptosis through a p53-dependent pathway.
• Targeting AC represents a promising strategy to improve radiotherapy efficacy for locally advanced rectal cancer.