title: Gene polymorphisms in antioxidant enzymes correlate with the efficacy of androgen-deprivation therapy for prostate cancer with implications of oxidative stress.
abstract: Oxidative stress mitigated by antioxidant enzymes is thought to be involved in the progression to castration-resistant prostate cancer (CRPC) during androgen-deprivation therapy (ADT). This study investigated the association between genetic variations in antioxidant enzymes and the efficacy of ADT as well as its biological background.
  
  
  
  The non-synonymous or promoter-locating polymorphisms of antioxidant enzymes were examined as well as the time to CRPC progression and overall survival in 104 and 92 patients treated with ADT for metastatic and non-metastatic prostate cancer, respectively. In addition, intracellular reactive oxygen species and expression levels of antioxidant enzymes were examined in castration-resistant and enzalutamide-resistant cells.
  
  
  
  In metastatic prostate cancer, the AG/GG allele in GSTM3 rs7483 and CT/TT allele in CAT rs564250 were associated with a significantly lower risk of progression to CRPC and all-cause death compared with homozygotes of the major AA allele (hazard ratio [HR]; [95% confidence interval (CI)], 0.55 [0.34-0.86], P = 0.0086) and CC allele (HR; [95% CI], 0.48 [0.24-0.88], P = 0.016), respectively. On multivariate analyses, only GSTM3 rs7483 was associated with significant progression risk (AG/GG versus AA; HR; [95% CI], 0.45 [0.25-0.79], P = 0.0047) even after Bonferroni adjustment. In non-metastatic prostate cancer, the AG/GG allele in GSTM3 rs7483 was associated with a significantly lower risk of progression to CRPC (HR; [95% CI], 0.35 [0.10-0.93], P = 0.034) and all-cause death (HR; [95% CI], 0.26 [0.041-0.96], P = 0.043) compared with the AA allele. Intracellular reactive oxygen species levels were increased, accompanied with augmented GSTM3 expression in both castration-resistant and enzalutamide-resistant cells.
  
  
  
  Differential activity of antioxidant enzymes caused by the polymorphism in GSTM3 may contribute to resistance to hormonal therapy through oxidative stress. The GSTM3 rs7483 polymorphism may be a promising biomarker for prostate cancer patients treated with ADT.
authors.affiliation: Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Shiota
authors.affiliation: Department of Urology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Fujimoto
authors.affiliation: Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Itsumi
authors.affiliation: Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Takeuchi
authors.affiliation: Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: J
authors.initials: J
authors.lastname: Inokuchi
authors.affiliation: Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Tatsugami
authors.affiliation: Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Yokomizo
authors.affiliation: Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Kajioka
authors.affiliation: Department of Clinical Chemistry and Laboratory Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Uchiumi
authors.affiliation: Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Eto
mesh_terms: D000368:Aged; D000483:Alleles; D000726:Androgen Antagonists / Q000008:administration & dosage; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage; D000975:Antioxidants / Q000008:administration & dosage; D001549:Benzamides; D002374:Catalase / Q000235:genetics; D018450:Disease Progression; D018572:Disease-Free Survival; D005982:Glutathione Transferase / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009570:Nitriles; D018384:Oxidative Stress / Q000187:drug effects* / Q000235:genetics; D010669:Phenylthiohydantoin / Q000008:administration & dosage / Q000031:analogs & derivatives; D016016:Proportional Hazards Models; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology
chemical_list: D000726:Androgen Antagonists; D018931:Antineoplastic Agents, Hormonal; D000975:Antioxidants; D001549:Benzamides; D009570:Nitriles; D010669:Phenylthiohydantoin; C540278:enzalutamide; D002374:Catalase; C483009:GSTM3 protein, human; D005982:Glutathione Transferase
keywords: androgen-deprivation therapy; castration-resistant prostate cancer; catalase; glutathione S-transferase; single-nucleotide polymorphism