Docosahexaenoic acid induces autophagy through p53/AMPK/mTOR signaling and promotes apoptosis in human cancer cells harboring wild-type p53

Abstract

Docosahexaenoic acid (DHA) has been reported to induce tumor cell death by apoptosis. However, little is known about the effects of DHA on autophagy, another complex well-programmed process characterized by the sequestration of cytoplasmic material within autophagosomes. Here, we show that DHA increased both the level of microtubule-associated protein light-chain 3 and the number of autophagic vacuoles without impairing autophagic vesicle turnover, indicating that DHA induces not only apoptosis but also autophagy. We also observed that DHA-induced autophagy was accompanied by p53 loss. Inhibition of p53 increased DHA-induced autophagy and prevention of p53 degradation significantly led to the attenuation of DHA-induced autophagy, suggesting that DHA-induced autophagy is mediated by p53. Further experiments showed that the mechanism of DHA-induced autophagy associated with p53 attenuation involved an increase in the active form of AMP-activated protein kinase and a decrease in the activity of mammalian target of rapamycin. In addition, compelling evidence for the interplay between autophagy and apoptosis induced by DHA is supported by the findings that autophagy inhibition suppressed apoptosis and further autophagy induction enhanced apoptosis in response to DHA treatment. Overall, our results demonstrate that autophagy contributes to the cytotoxicity of DHA in cancer cells harboring wild-type p53.

The HSP70 and Autophagy Inhibitor Pifithrin-μ Enhances the Antitumor Effects of TRAIL on Human Pancreatic Cancer

“…Despite the reports of autophagic cell death (18,35,36) and autophagy-dependent antitumor immune response (37), the fundamental role of autophagy is thought to be cytoprotection under starvation and stress conditions (16). Many reports suggest that autophagy functions cytoprotectively in cancer cells (19,20,36,38). In line with this, we previously reported that autophagy protects against apoptosis in human prostate and breast cancer cells after treatment with an innate adjuvant receptor ligand (21,22).…”

“…Autophagy has received much attention in various cell biology fields (16,17). Despite the reports of autophagic cell death (18,35,36) and autophagy-dependent antitumor immune response (37), the fundamental role of autophagy is thought to be cytoprotection under starvation and stress conditions (16). Many reports suggest that autophagy functions cytoprotectively in cancer cells (19,20,36,38).…”

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.…”

mTOR plays a critical role in p53-induced oxidative kidney cell injury in HIVAN

“…p53 inhibits mTOR by activation of AMP-activated protein kinase (AMPK) and subsequent regulation of the TSC1/TSC2 complex (21). Inactivation of either TSC1/TSC2 complex or AMPK inhibits the impact of p53 on mTOR pathway (21).…”