A Basal Level of γ-Linolenic Acid Depletes Ca2+ Stores and Induces Endoplasmic Reticulum and Oxidative Stresses to Cause Death of Breast Cancer BT-474 Cells

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Gamma-linolenic acid (GLA), a natural fatty acid obtained from oils of various vegetables and seeds, has been demonstrated as an anticancer agent. In this work, we investigated the anticancer effects of GLA on breast cancer BT-474 cells. GLA at 30 μM, a concentration reportedly within the range of circulating concentrations in clinical studies, caused apoptotic cell death. GLA caused an elevation in mitochondrial Ca 2+ level and a decrease in mitochondrial membrane potential. GLA treatment depleted cyclopiazonic acid (CPA)-sensitive Ca 2+ store and triggered substantial Ca 2+ influx. Intracellular Ca 2+ release triggered by GLA was suppressed by 3 μM xestospongin C (XeC, IP 3 receptor-channel blocker) and 100 μM ryanodine (ryanodine receptor-channel blocker), suggesting that the Ca 2+ release was via IP 3 receptor-channel and ryanodine receptor-channel. Increased expressions of p-eIF2α and CHOP were observed in GLA-treated cells, suggesting GLA-treated cells had increased expressions of p-eIF2α and CHOP, which suggest endoplasmic reticulum (ER) stress. In addition, GLA elicited increased production of reactive oxygen species. Taken together, our results suggest a basal level of GLA induced apoptotic cell death by causing Ca 2+ overload, mitochondrial dysfunction, Ca 2+ store depletion, ER stress, and oxidative stress. This is the first report to show that GLA caused Ca 2+ store depletion and ER stress. GLA-induced Ca 2+ store depletion resulted from opening of IP 3 receptor-channel and ryanodine receptor-channel.