title: 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.
authors.affiliation: Department of Biochemistry, College of Medicine, Chungnam National University, Daejeon 301-747, Republic of Korea.
authors.forename: Soyeon
authors.initials: S
authors.lastname: Shin
authors.forename: Kaipeng
authors.initials: K
authors.lastname: Jing
authors.forename: Soyeon
authors.initials: S
authors.lastname: Jeong
authors.forename: Nayeong
authors.initials: N
authors.lastname: Kim
authors.forename: Kyoung-Sub
authors.initials: KS
authors.lastname: Song
authors.forename: Jun-Young
authors.initials: JY
authors.lastname: Heo
authors.forename: Ji-Hoon
authors.initials: JH
authors.lastname: Park
authors.forename: Kang-Sik
authors.initials: KS
authors.lastname: Seo
authors.forename: Jeongsu
authors.initials: J
authors.lastname: Han
authors.forename: Jong-Il
authors.initials: JI
authors.lastname: Park
authors.forename: Gi-Ryang
authors.initials: GR
authors.lastname: Kweon
authors.forename: Seung-Kiel
authors.initials: SK
authors.lastname: Park
authors.forename: Tong
authors.initials: T
authors.lastname: Wu
authors.forename: Byung-Doo
authors.initials: BD
authors.lastname: Hwang
authors.forename: Kyu
authors.initials: K
authors.lastname: Lim
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D045744:Cell Line, Tumor; D004281:Docosahexaenoic Acids; D015525:Fatty Acids, Omega-3 / Q000008:administration & dosage* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D051058:Oncogene Protein v-akt / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D015525:Fatty Acids, Omega-3; D017382:Reactive Oxygen Species; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D004281:Docosahexaenoic Acids; C546842:MTOR protein, human; D051058:Oncogene Protein v-akt; D058570:TOR Serine-Threonine Kinases