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Docosahexaenoic acid increases the expression of oxidative stress-induced growth inhibitor 1 through the PI3K/Akt/Nrf2 signaling pathway in breast cancer cells

Tsai, Chia-Han, Shen, You-Cheng, Chen, Haw-Wen, Liu, Kai-Li, Chang, Jer-Wei, Chen, Pei-Yin, Lin, Chen-Yu, Yao, Hsien-Tsung, Li, Chien-Chun
Food and chemical toxicology 2017 v.108 pp. 276-288
acetylcysteine, alpha-linolenic acid, apoptosis, arachidonic acid, breast neoplasms, cell proliferation, cytochrome c, docosahexaenoic acid, eicosapentaenoic acid, gamma-linolenic acid, gene expression, growth inhibitors, linoleic acid, messenger RNA, mitochondria, neoplasm cells, omega-3 fatty acids, phosphatidylinositol 3-kinase, phosphorylation, protein synthesis, reactive oxygen species, signal transduction, toxicology
Oxidative stress-induced growth inhibitor 1 (OSGIN1), a tumor suppressor, inhibits cell proliferation and induces cell death. N-6 and n-3 PUFAs protect against breast cancer, but the molecular mechanisms of this effect are not clear. We investigated the effect of n-6 and n-3 PUFAs on OSGIN1 expression and whether OSGIN1 is involved in PUFA-induced apoptosis in breast cancer cells. We used 100 μM of n-6 PUFAs including arachidonic acid, linoleic acid, and gamma-linolenic acid and n-3 PUFAs including alpha-linolenic acid, eicosapentaenoic acid, and docosahexaenoic acid (DHA). Only DHA significantly induced OSGIN1 protein and mRNA expression. DHA triggered reactive oxygen species (ROS) generation and nuclear translocation of Nrf2. LY294002, a PI3K inhibitor, suppressed DHA-induced OSGIN1 protein expression and nuclear accumulation of Nrf2. Nrf2 knockdown attenuated DHA-induced OSGIN1 expression. N-Acetyl-l-cysteine, a ROS scavenger, abrogated the DHA-induced increases in Akt phosphorylation, Nrf2 nuclear accumulation, and OSGIN1 expression. DHA induced the Bax/Bcl-2 ratio, mitochondrial accumulation of OSGIN1 and p53, and cytochrome c release; knockdown of OSGIN1 diminished these effects. In conclusion, induction of OSGIN1 by DHA is at least partially associated with increased ROS production, which activates PI3K/Akt/Nrf2 signaling. Induction of OSGIN1 may be involved in DHA-induced apoptosis in breast cancer cells.