title: Docosahexaenoic acid-induced apoptosis is mediated by activation of mitogen-activated protein kinases in human cancer cells.
abstract: BACKGROUND
  The role of omega-3 polyunsaturated fatty acids (ω3-PUFAs) in cancer prevention has been demonstrated; however, the exact molecular mechanisms underlying the anticancer activity of ω3-PUFAs are not fully understood. Here, we investigated the relationship between the anticancer action of a specific ω3-PUFA docosahexaenoic acid (DHA), and the conventional mitogen-activated protein kinases (MAPKs) including extracellular signal-regulated kinase (ERK), c-JUN N-terminal kinase (JNK) and p38 whose dysregulation has been implicated in human cancers.
  
  
  METHODS
  MTT assays were carried out to determine cell viability of cancer cell lines (PA-1, H1299, D54MG and SiHa) from different origins. Apoptosis was confirmed by TUNEL staining, DNA fragmentation analysis and caspase activity assays. Activities of the conventional MAPKs were monitored by their phosphorylation levels using immunoblotting and immunocytochemistry analysis. Reactive oxygen species (ROS) production was measured by flow cytometry and microscopy using fluorescent probes for general ROS and mitochondrial superoxide.
  
  
  RESULTS
  DHA treatment decreased cell viability and induced apoptotic cell death in all four studied cell lines. DHA-induced apoptosis was coupled to the activation of the conventional MAPKs, and knockdown of ERK/JNK/p38 by small interfering RNAs reduced the apoptosis induced by DHA, indicating that the pro-apoptotic effect of DHA is mediated by MAPKs activation. Further study revealed that the DHA-induced MAPKs activation and apoptosis was associated with mitochondrial ROS overproduction and malfunction, and that ROS inhibition remarkably reversed these effects of DHA.
  
  
  CONCLUSIONS
  Together, these results indicate that DHA-induced MAPKs activation is dependent on its capacity to provoke mitochondrial ROS generation, and accounts for its cytotoxic effect in human cancer cells.
authors.forename: Soyeon
authors.initials: S
authors.lastname: Jeong
authors.forename: Kaipeng
authors.initials: K
authors.lastname: Jing
authors.forename: Nayeong
authors.initials: N
authors.lastname: Kim
authors.forename: Soyeon
authors.initials: S
authors.lastname: Shin
authors.forename: Soyeon
authors.initials: S
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: 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: Jong-Il
authors.initials: JI
authors.lastname: Park
authors.affiliation: Department of Biochemistry, School of Medicine, Chungnam National University, Daejeon 301-747, Korea. kyulim@cnu.ac.kr.
authors.forename: Kyu
authors.initials: K
authors.lastname: Lim
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009369:Neoplasms / Q000201:enzymology* / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; D004281:Docosahexaenoic Acids; D020928:Mitogen-Activated Protein Kinases