title: Testosterone promotes DNA damage response under oxidative stress in prostate cancer cell lines.
abstract: BACKGROUND
  Sustained chronic inflammation and oxidative stress in the prostate promote prostate carcinogenesis. The process of oncogenic transformation leads to enhanced DNA damage and activates the checkpoint network that functions as an inducible barrier against cancer progression. Here, we analyzed the effects of testosterone on the DNA damage response in prostate cancer cells to assess whether testosterone functions a barrier to cancer progression under the oxidative stress.
  
  
  METHODS
  We examined the effects of testosterone on components of the DNA damage response pathway, including ATM (ataxia-telangiectasia-mutated kinase), H2AX (histone H2AX variant), and Chk2 (checkpoint kinase2) in prostate cancer cell lines, treated with various concentration of hydrogen peroxide (H(2) O(2) ). Cellular apoptosis was quantified by poly (ADP-ribose) polymerase (PARP) cleavage and flow cytometry.
  
  
  RESULTS
  H(2) O(2) induced apoptosis and phosphorylation of ATM, Chk2, and H2AX in LNCaP cells. An ATM inhibitor, Ku55933, reduced H(2) O(2) -induced apoptosis in LNCaP and 22Rv1 cells. Androgen treatments increased H(2) O(2) -induced activation of the DNA damage response and PARP cleavage, but not when the H(2) O(2) -treated cells were also treated with the anti-androgen flutamide. The ATM inhibitor Ku55933 inhibited androgen-induced phosphorylation of ATM and PARP cleavage.
  
  
  CONCLUSIONS
  DNA damage responses play important roles in the maintenance of the cell homeostasis in response to oxidative stress. Our results indicated that under oxidative stress androgen signaling may induce apoptosis by activating the DNA damage response.
authors.affiliation: Department of Urology, Teikyo University School of Medicine, Itabashi-ku, Tokyo, Japan. ihisamit@med.teikyo-u.ac.jp
authors.forename: Hisamitsu
authors.initials: H
authors.lastname: Ide
authors.forename: Yan
authors.initials: Y
authors.lastname: Lu
authors.forename: Jingsong
authors.initials: J
authors.lastname: Yu
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: China
authors.forename: Tomoka
authors.initials: T
authors.lastname: Kumamoto
authors.forename: Tatsuro
authors.initials: T
authors.lastname: Koseki
authors.forename: Raizo
authors.initials: R
authors.lastname: Yamaguchi
authors.forename: Satoru
authors.initials: S
authors.lastname: Muto
authors.forename: Shigeo
authors.initials: S
authors.lastname: Horie
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D064007:Ataxia Telangiectasia Mutated Proteins; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D064447:Checkpoint Kinase 2; D004249:DNA Damage / Q000187:drug effects* / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects* / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects; D011467:Prostate / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D013739:Testosterone / Q000494:pharmacology*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C468783:H2AX protein, human; D006657:Histones; D025521:Tumor Suppressor Proteins; D013739:Testosterone; D006861:Hydrogen Peroxide; D064447:Checkpoint Kinase 2; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C578634:CHEK2 protein, human; D017346:Protein Serine-Threonine Kinases