title: 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.
authors.affiliation: Department of Biochemistry, College of Medicine, Chungnam National University, Daejeon, Korea.
authors.forename: Kaipeng
authors.initials: K
authors.lastname: Jing
authors.forename: Kyoung-Sub
authors.initials: KS
authors.lastname: Song
authors.forename: Soyeon
authors.initials: S
authors.lastname: Shin
authors.forename: Nayeong
authors.initials: N
authors.lastname: Kim
authors.forename: Soyeon
authors.initials: S
authors.lastname: Jeong
authors.forename: Hye-Rim
authors.initials: HR
authors.lastname: Oh
authors.forename: Ji-Hoon
authors.initials: JH
authors.lastname: Park
authors.forename: Kang-Sik
authors.initials: KS
authors.lastname: Seo
authors.forename: Jun-Young
authors.initials: JY
authors.lastname: Heo
authors.forename: Jeongsu
authors.initials: J
authors.lastname: Han
authors.forename: Jong-Il
authors.initials: JI
authors.lastname: Park
authors.forename: Chang
authors.initials: C
authors.lastname: Han
authors.forename: Tong
authors.initials: T
authors.lastname: Wu
authors.forename: Gi-Ryang
authors.initials: GR
authors.lastname: Kweon
authors.forename: Seung-Kiel
authors.initials: SK
authors.lastname: Park
authors.forename: Wan-Hee
authors.initials: WH
authors.lastname: Yoon
authors.forename: Byung-Doo
authors.initials: BD
authors.lastname: Hwang
authors.forename: Kyu
authors.initials: K
authors.lastname: Lim
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D055785:Gene Knockdown Techniques; D006801:Humans; D008954:Models, Biological; D059748:Proteolysis / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D016159:Tumor Suppressor Protein p53; D004281:Docosahexaenoic Acids; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D053148:Caspase 3