Repression of cellular anaplerosis as the hypothesized mechanism of gamma-linolenic acid-induced toxicity to tumor cells.
In in vitro cultures, the cell is virtually isolated and can no longer rely on mechanisms for physiological regulation of substrate availability found in tissues. More emphasis is laid on utilization of preponderant substrate in a proposed reciprocal relationship between glycolysis and free fatty acid (FFA) oxidation for energy. Supraphysiological concentrations of gamma-linolenic acid and some other polyunsaturated fatty acids (PUFAs) therefore suppress glycolysis but also inhibit FFA oxidation initiated through a cytochrome P450-mediated epoxidation of PUFA to inhibit fatty acid synthase (FAS) activity. FAS inhibition accumulates malonyl CoA which inhibits carnitine palmitoyl transferase I and prevents FFA oxidation. The cell is starved of energy and anabolic intermediates, leading to decreased proliferation or death for tumor cells. Tumor cells are more vulnerable to this induced toxicity due to possession of specific phenotypes of elevated expression for FAS and pyruvate kinase, type M2, both factors inducing tumor cell apoptosis on inhibition.
Nwankwo
J O
JO
Department of Biochemistry, College of Medicine, University of Iowa, IA, USA. joseph-nwankwo@uiowa.edu
D000105:Acetyl Coenzyme A / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004852:Epoxy Compounds / Q000494:pharmacology; D064429:Fatty Acid Synthases / Q000037:antagonists & inhibitors; D005227:Fatty Acids / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D006801:Humans; D014407:Tumor Cells, Cultured; D017965:gamma-Linolenic Acid / Q000494:pharmacology*
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D004852:Epoxy Compounds; D005227:Fatty Acids; D000105:Acetyl Coenzyme A; D017965:gamma-Linolenic Acid; D003577:Cytochrome P-450 Enzyme System; D064429:Fatty Acid Synthases; D005947:Glucose