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 ac id (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 cyt ochrome P450-mediated epoxidation of PUFA to inhibit fatty acid synthase (F AS) activity. FAS inhibition accumulates malonyl CoA which inhibits carniti ne 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 tox icity due to possession of specific phenotypes of elevated expression for F AS and pyruvate kinase, type M2, both factors inducing tumor cell apoptosis on inhibition. (C) 2001 Harcourt Publishers Ltd.