title: Resveratrol induces apoptosis of human chronic myelogenous leukemia cells in vitro through p38 and JNK-regulated H2AX phosphorylation.
abstract: OBJECTIVE
  The phosphorylation of histone H2AX, a novel tumor suppressor protein, is involved in regulation of cancer cell apoptosis. The aim of this study was to examine whether H2AX phosphorylation was required for resveratrol-induced apoptosis of human chronic myelogenous leukemia (CML) cells in vitro.
  
  
  METHODS
  K562 cells were tested. Cell apoptosis was analyzed using flow cytometry, and the phosphorylation of H2AX and other signaling proteins was examined with Western blotting. To analyze the signaling pathways, the cells were transfected with lentiviral vectors encoding H2AX-wt or specific siRNAs.
  
  
  RESULTS
  Treatment of K562 cells with resveratrol (20-100 μmol/L) induced apoptosis and phosphorylation of H2AX at Ser139 in time- and dose-dependent manners, but reduced phosphorylation of histone H3 at Ser10. Resveratrol treatment activated two MAPK family members p38 and JNK, and blocked the activation of another MAPK family member ERK. Pretreatment with the p38 inhibitor SB202190 or the JNK inhibitor SP600125 dose-dependently reduced resveratrol-induced phosphorylation of H2AX, which were also observed when the cells were transfected with p38- or JNK-specific siRNAs. Overexpression of H2AX in K562 cells markedly increased resveratrol-induced apoptosis, whereas overexpression of H2AX-139m (Ser139 was mutated to block phosphorylation) inhibited resveratrol-induced apoptosis. K562 cells transfected with H2AX-specific siRNAs were resistant to resveratrol-induced apoptosis.
  
  
  CONCLUSIONS
  H2AX phosphorylation at Ser139 in human CML cells, which is regulated by p38 and JNK, is essential for resveratrol-induced apoptosis.
authors.affiliation: 1] Clinical School of Air Force General Hospital, Anhui Medical University, Heifei 230000, China [2] Aviation Medicine Research Laboratory, Air Force General Hospital, PLA, Beijing 100142, China.
authors.forename: Xin-pin
authors.initials: XP
authors.lastname: Wu
authors.affiliation: Aviation Medicine Research Laboratory, Air Force General Hospital, PLA, Beijing 100142, China.
authors.forename: Min
authors.initials: M
authors.lastname: Xiong
authors.affiliation: Aviation Medicine Research Laboratory, Air Force General Hospital, PLA, Beijing 100142, China.
authors.forename: Cheng-shan
authors.initials: CS
authors.lastname: Xu
authors.affiliation: Aviation Medicine Research Laboratory, Air Force General Hospital, PLA, Beijing 100142, China.
authors.forename: Lian-ning
authors.initials: LN
authors.lastname: Duan
authors.affiliation: Aviation Medicine Research Laboratory, Air Force General Hospital, PLA, Beijing 100142, China.
authors.forename: Ya-qiong
authors.initials: YQ
authors.lastname: Dong
authors.affiliation: Aviation Medicine Research Laboratory, Air Force General Hospital, PLA, Beijing 100142, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Luo
authors.affiliation: Aviation Medicine Research Laboratory, Air Force General Hospital, PLA, Beijing 100142, China.
authors.forename: Tian-hui
authors.initials: TH
authors.lastname: Niu
authors.affiliation: 1] Clinical School of Air Force General Hospital, Anhui Medical University, Heifei 230000, China [2] Aviation Medicine Research Laboratory, Air Force General Hospital, PLA, Beijing 100142, China.
authors.forename: Cheng-rong
authors.initials: CR
authors.lastname: Lu
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034622:RNA Interference; D000077185:Resveratrol; D015398:Signal Transduction / Q000187:drug effects; D013267:Stilbenes / Q000494:pharmacology*; D013997:Time Factors; D014162:Transfection; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; C468783:H2AX protein, human; D006657:Histones; D047428:Protein Kinase Inhibitors; D013267:Stilbenes; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D000077185:Resveratrol