Gene polymorphisms in antioxidant enzymes correlate with the efficacy of androgen-deprivation therapy for prostate cancer with implications of oxidative stress

Masaki Shiota, N. Fujimoto, M. Itsumi, A. Takeuchi, J. Inokuchi, K. Tatsugami, A. Yokomizo, S. Kajioka, T. Uchiumi, M. Eto

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Abstract

Background: Oxidative stress mitigated by antioxidant enzymes is thought to be involved in the progression to castrationresistant 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. Patients and methods: 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 nonmetastatic prostate cancer, respectively. In addition, intracellular reactive oxygen species and expression levels of antioxidant enzymes were examined in castration-resistant and enzalutamide-resistant cells. Results: 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. Conclusions: 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.

Original languageEnglish
Pages (from-to)569-575
Number of pages7
JournalAnnals of Oncology
Volume28
Issue number3
DOIs
Publication statusPublished - Jan 1 2017

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Androgens
Prostatic Neoplasms
Oxidative Stress
Antioxidants
Alleles
Enzymes
Genes
Confidence Intervals
Castration
Therapeutics
Cause of Death
Reactive Oxygen Species
Homozygote
Multivariate Analysis
Biomarkers
Survival

All Science Journal Classification (ASJC) codes

  • Hematology
  • Oncology

Cite this

@article{8602f84ac6094f7fb2b36bf595466ac0,
title = "Gene polymorphisms in antioxidant enzymes correlate with the efficacy of androgen-deprivation therapy for prostate cancer with implications of oxidative stress",
abstract = "Background: Oxidative stress mitigated by antioxidant enzymes is thought to be involved in the progression to castrationresistant 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. Patients and methods: 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 nonmetastatic prostate cancer, respectively. In addition, intracellular reactive oxygen species and expression levels of antioxidant enzymes were examined in castration-resistant and enzalutamide-resistant cells. Results: 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. Conclusions: 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.",
author = "Masaki Shiota and N. Fujimoto and M. Itsumi and A. Takeuchi and J. Inokuchi and K. Tatsugami and A. Yokomizo and S. Kajioka and T. Uchiumi and M. Eto",
year = "2017",
month = "1",
day = "1",
doi = "10.1093/annonc/mdw646",
language = "English",
volume = "28",
pages = "569--575",
journal = "Annals of Oncology",
issn = "0923-7534",
publisher = "Oxford University Press",
number = "3",

}

TY - JOUR

T1 - Gene polymorphisms in antioxidant enzymes correlate with the efficacy of androgen-deprivation therapy for prostate cancer with implications of oxidative stress

AU - Shiota, Masaki

AU - Fujimoto, N.

AU - Itsumi, M.

AU - Takeuchi, A.

AU - Inokuchi, J.

AU - Tatsugami, K.

AU - Yokomizo, A.

AU - Kajioka, S.

AU - Uchiumi, T.

AU - Eto, M.

PY - 2017/1/1

Y1 - 2017/1/1

N2 - Background: Oxidative stress mitigated by antioxidant enzymes is thought to be involved in the progression to castrationresistant 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. Patients and methods: 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 nonmetastatic prostate cancer, respectively. In addition, intracellular reactive oxygen species and expression levels of antioxidant enzymes were examined in castration-resistant and enzalutamide-resistant cells. Results: 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. Conclusions: 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.

AB - Background: Oxidative stress mitigated by antioxidant enzymes is thought to be involved in the progression to castrationresistant 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. Patients and methods: 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 nonmetastatic prostate cancer, respectively. In addition, intracellular reactive oxygen species and expression levels of antioxidant enzymes were examined in castration-resistant and enzalutamide-resistant cells. Results: 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. Conclusions: 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.

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U2 - 10.1093/annonc/mdw646

DO - 10.1093/annonc/mdw646

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VL - 28

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JO - Annals of Oncology

JF - Annals of Oncology

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