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

Abstract

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 Ca2+ level and a decrease in mitochondrial membrane potential. GLA treatment depleted cyclopiazonic acid (CPA)-sensitive Ca2+ store and triggered substantial Ca2+ influx. Intracellular Ca2+ release triggered by GLA was suppressed by 3 μM xestospongin C (XeC, IP3 receptor-channel blocker) and 100 μM ryanodine (ryanodine receptor-channel blocker), suggesting that the Ca2+ release was via IP3 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 Ca2+ overload, mitochondrial dysfunction, Ca2+ store depletion, ER stress, and oxidative stress. This is the first report to show that GLA caused Ca2+ store depletion and ER stress. GLA-induced Ca2+ store depletion resulted from opening of IP3 receptor-channel and ryanodine receptor-channel.

Poly-Unsaturated Fatty Acids (PUFAs) from Cunninghamella elegans Grown on Glycerol Induce Cell Death and Increase Intracellular Reactive Oxygen Species

“…Alakhras et al (2016) observed synergistic actions between H 2 O 2 , which is a ROS source, and C. echinulata FALS [24]. C. echinulata and C. elegans both produce PUFAs high in GLA, and the latter has already been correlated to the accumulation of ROS and lipid peroxidation [20,57,58]. Our study measured the direct elevation of intracellular ROS levels following treatment with FALS and found them to be significantly elevated.…”

DPP3 promotes breast cancer tumorigenesis by stabilizing FASN and promoting lipid synthesis

“… Neuroblastoma Cell line Reduce oxidative stress levels [42] . gamma-Linolenic acid C18H30O2 Breast cancer Cell line Deplete Ca2+ stores and induces endoplasmic reticulum and oxidative stresses to cause death of breast cancer BT-474 cells [43] . Cell line Reduce the expression and secretion of SPARC [44] .…”

“…Deplete Ca2+ stores and induces endoplasmic reticulum and oxidative stresses to cause death of breast cancer BT-474 cells [43] .…”

Excessive ER-phagy mediated by FAM134B contributes to trophoblast cell mitochondrial dysfunction in preeclampsia

“…In this study, GLA was shown to play an important role in mitochondrial apoptosis after FAM134B overexpression. The proposed primary mechanism for apoptosis induction by GLA deficiency is oxidative stress, which is attributed to Ca 2+ overload, mitochondrial dysfunction, Ca 2+ store depletion [57], ROS accumulation, and lipid peroxidation [58]. Our previous research indicated that polyunsaturated omega-3 and omega-6 fatty acids, including GLA, DHA, and DPA, in mitochondria might be involved in dysregulating PE placentas [59].…”