Peroxisomal lipid metabolism inhibits Pimozide-induced cancer cell death by regulating ATP homeostasis

Area of Science:

• Cell Biology
• Cancer Metabolism
• Drug Discovery

Background:

• Antipsychotic drugs show potential in cancer therapy by inhibiting tumor growth and inducing cell death.
• The precise mechanisms by which tumor cells respond to antipsychotics like pimozide are not fully understood.
• Pimozide, an FDA-approved antipsychotic, presents a promising candidate for novel cancer treatments.

Purpose of the Study:

• To investigate the role of peroxisomes in mediating tumor cell resistance to pimozide.
• To elucidate the molecular mechanisms by which peroxisomes influence cell death pathways induced by pimozide.

Main Methods:

• Quantification of peroxisome numbers in tumor cells treated with pimozide.
• Assessment of cell viability and apoptosis in peroxisomal-deficient and control cells exposed to pimozide.
• Analysis of metabolic pathways, including fatty acid oxidation, ether lipid synthesis, and reactive oxygen species (ROS) metabolism, within peroxisomes.
• Evaluation of peroxisomal lipid-metabolizing enzyme expression levels.

Main Results:

• Pimozide treatment leads to an increase in peroxisome abundance in tumor cells.
• Disruption of peroxisomal function significantly enhances pimozide-induced apoptosis.
• Peroxisomes primarily counteract pimozide-induced cell death via fatty acid oxidation and ether lipid synthesis, not ROS metabolism.
• Pimozide upregulates key peroxisomal lipid-metabolizing enzymes.

Conclusions:

• Peroxisomes play a crucial role in conferring resistance to pimozide in tumor cells.
• Peroxisomal metabolic activities, particularly lipid metabolism, are vital for maintaining energy homeostasis and preventing pimozide-induced apoptosis.
• Targeting peroxisomal pathways could represent a novel strategy to enhance the efficacy of pimozide in cancer therapy.