title: Role of JNK and p38 MAPK in Taiwanin A-induced cell death.
abstract: OBJECTIVE
  The lignan compound Taiwanin A is cytotoxic for human cancer cells. Taiwanin A has been previously shown to damage microtubules, induce mitotic arrest and cause apoptosis in cancer cells. The goal of the current study is to identify intracellular signaling pathways that are involved in Taiwanin A-mediated apoptosis.
  
  
  METHODS
  We examined the activation of three mitogen-activated protein kinases (MAPKs), extracellular signal-regulated kinase (ERK), p38 and c-Jun N-terminal kinase (JNK), in HepG2 cells after Taiwanin A treatment. The role of MAPK activation in Taiwanin A-induced apoptosis was examined using Western blotting, caspase activity assays combined with specific MAPK inhibitors and shRNA treatment to knockdown JNK.
  
  
  RESULTS
  Taiwanin A activated all three MAPKs (ERK, p38 and JNK). Cytotoxicity was blocked by the p38 MAPK inhibitor SB203580 and the JNK inhibitor SP600125 but not by the ERK inhibitor PD98059. A combined treatment of SB203580 and SP600125 showed increased effects on the inhibition of Taiwanin A cytotoxicity, suggesting that both JNK and p38 play a role in Taiwanin A-induced apoptosis. Inhibition of p38 activity reduced Taiwanin A-induced p53 phosphorylation on Ser15. Direct interaction of Taiwanin A-activated p38 and p53 was demonstrated by immunoprecipitation. In addition, inhibition of JNK by SP600125 or silencing of the JNK scaffold protein JIP2 reduced phosphorylation of Bcl-2, which may help to promote anti-apoptotic pathways.
  
  
  CONCLUSIONS
  We demonstrated for the first time that two distinct apoptotic pathways, the p38-p53 and JNK-Bcl-2 pathways, were triggered by the anti-microtubule compound Taiwanin A.
authors.affiliation: Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, Taiwan, ROC.
authors.forename: Pai-Jiun
authors.initials: PJ
authors.lastname: Ho
authors.forename: Chen-Kung
authors.initials: CK
authors.lastname: Chou
authors.forename: Sheau-Farn
authors.initials: SF
authors.lastname: Yeh
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D005663:Furans / Q000494:pharmacology*; D055785:Gene Knockdown Techniques; D056945:Hep G2 Cells; D006801:Humans; D047468:Immunoprecipitation; D048031:JNK Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism; D017705:Lignans / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D016159:Tumor Suppressor Protein p53 / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D005663:Furans; D017705:Lignans; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; C419332:taiwanin A; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases