The Omega-3 Polyunsaturated Fatty Acid DHA Induces Simultaneous Apoptosis and Autophagy via Mitochondrial ROS-Mediated Akt-mTOR Signaling in Prostate Cancer Cells Expressing Mutant p53

Abstract

Docosahexaenoic acid (DHA) induces autophagy-associated apoptotic cell death in wild-type p53 cancer cells via regulation of p53. The present study investigated the effects of DHA on PC3 and DU145 prostate cancer cell lines harboring mutant p53. Results show that, in addition to apoptosis, DHA increased the expression levels of lipidated form LC3B and potently stimulated the autophagic flux, suggesting that DHA induces both autophagy and apoptosis in cancer cells expressing mutant p53. DHA led to the generation of mitochondrial reactive oxygen species (ROS), as shown by the mitochondrial ROS-specific probe mitoSOX. Similarly, pretreatment with the antioxidant N-acetyl-cysteine (NAC) markedly inhibited both the autophagy and the apoptosis triggered by DHA, indicating that mitochondrial ROS mediate the cytotoxicity of DHA in mutant p53 cells. Further, DHA reduced the levels of phospho-Akt and phospho-mTOR in a concentration-dependent manner, while NAC almost completely blocked that effect. Collectively, these findings present a novel mechanism of ROS-regulated apoptosis and autophagy that involves Akt-mTOR signaling in prostate cancer cells with mutant p53 exposed to DHA.

The marine n-3 PUFA DHA evokes cytoprotection against oxidative stress and protein misfolding by inducing autophagy and NFE2L2 in human retinal pigment epithelial cells

“…Previously, several reports have suggested a change in autophagy in cancer cell lines that are sensitive and display cytotoxic and/or cytostatic responses to physiological doses of PUFAs. [48][49][50][51][52][53] We explore whether increased autophagy is a part of the cellular response to PUFAs also in spontaneously arising ARPE-19 cells. If so, we hypothesize a correlation between the disease preventive effects of n-3 PUFAs and stimulation of autophagy in retinal pigment epithelial cells where the initial phases of AMD occurs.…”

Efeitos do ácido docosahexaenoico (DHA) e do ácido araquidônico (AA) sobre a morte celular da linhagem celular de câncer de mama MDA-MB-231

“…Diversas pesquisas já mostraram o efeito antitumoral in vitro e in vivo desse ácido graxo, porém, nenhuma delas avaliou a indução dos marcadores citados no presente estudo. (4,(33)(34)(35).…”

The Effect of Omega Fatty Acids on Bcl-2 Gene Expression and Protein Production in Cancerous Gastric Tissue

“…DHA and EPA elevated the expression of the PTEN gene and its protein, peroxisome proliferator-activated receptor gamma (PPARγ), in breast cancer cells. Increase of PPARγ resulted in inhibition of AKT-mTOR signaling phatways and cancer cell proliferation [22]. Gene n-3 PUFAs induce apoptosis and autophagy in prostate cancer cell lines through the AKT-mTOR signaling pathways [22].…”

“…Increase of PPARγ resulted in inhibition of AKT-mTOR signaling phatways and cancer cell proliferation [22]. Gene n-3 PUFAs induce apoptosis and autophagy in prostate cancer cell lines through the AKT-mTOR signaling pathways [22]. In addition to apoptosis, PUFAs suppress inflammatory process and modulate CD4+ T-cell differentiation [23].…”