Docosahexaenoic Acid Induces Death in Murine Leukemia Cells by Activating the Extrinsic Pathway of Apoptosis

Docosahexaenoic acid (DHA) is a unique fatty acid that is found predominantly in the phospholipids of cell membranes. It has wideranging therapeutic effects that are broadly appreciated but poorly understood. Its principal location in the membranes of cells suggests that these myriad effects are manifest there. When cultured in DHA-enriched medium, cells of the murine leukemia cell line T27A took up the fatty acid and incorporated it into cellular phospholipids, particularly those of the plasma membrane. Culture in DHA-enriched media also caused significant dose-dependent cell death accompanied by increased plasma membrane bleb formation. Cysteine-dependent aspartate-directed proteases (caspases)-3 -8 and -9 were also activated, establishing apoptosis as the mechanism of DHA-induced cell death. Inhibition of any one of these caspases rescued the cells from apoptotic death. Caspase inhibition experiments identified T27A cells as belonging to the type II group of apoptotic cells and showed that apoptosis was initiated via the extrinsic pathway. Together these and previous data support the hypothesis that DHA causes cell death in leukemic cells by inducing alterations in the structure of lipid rafts that lead to the ligand-independent activation of death receptors and apoptosis.