The polyunsaturated fatty acid docosahexaenoic affects mitochondrial function in prostate cancer cells

Area of Science:

• Mitochondrial biology
• Cancer metabolism
• Lipid biochemistry

Background:

• Prostate cancer (PCa) exhibits altered metabolism, with increased fatty acid synthesis and uptake linked to mitochondrial function.
• Docosahexaenoic acid (DHA), an omega-3 polyunsaturated fatty acid (PUFA), has known antitumoral effects, but its specific impact on prostate cancer mitochondria remains unclear.

Purpose of the Study:

• To investigate the modulatory effects of DHA on mitochondrial function in non-malignant and castration-resistant prostate cancer (CRPC) cell lines.

Main Methods:

• Seahorse extracellular flux assay for mitochondrial respiration.
• Radiolabeled glucose ([14C]-glucose) to assess oxidation and fatty acid synthesis.
• Metabolite profiling (1H-NMR), reactive oxygen species (ROS) detection (MitoSOX), and mitochondrial membrane potential assessment (JC-1).
• Analysis of phosphatidylglycerol composition, mitochondrial morphology (super-resolution microscopy, TEM), protein expression (COX-I, SDH-A), and cell death (Annexin V/7-AAD).

Main Results:

• DHA decreased basal respiration, ATP production, and spare respiratory capacity in all tested cell lines.
• DHA induced mitochondrial hyperpolarization, ROS overproduction, and altered phosphatidylglycerol composition, increasing membrane unsaturation.
• Metabolic shifts observed: increased glycolysis in PNT1A, stimulated glucose oxidation in cancer cells, and decreased de novo lipogenesis in 22Rv1 cells.
• DHA triggered cell death, particularly in PNT1A and 22Rv1 cells.

Conclusions:

• PUFA supplementation with DHA significantly impacts mitochondrial metabolism, impairing cell proliferation and survival.
• Targeting metabolism-related pathways, like de novo lipogenesis, in combination with DHA may offer a synergistic therapeutic strategy for CRPC.