Castration resistance of prostate cancer cells caused by castration-induced oxidative stress through Twist1 and androgen receptor overexpression

M. Shiota, Akira Yokomizo, Y. Tada, J. Inokuchi, E. Kashiwagi, D. Masubuchi, M. Eto, T. Uchiumi, S. Naito

Research output: Contribution to journalArticlepeer-review

96 Citations (Scopus)

Abstract

There are few successful therapies for castration-resistant prostate cancer (CRPC). Recently, CRPC has been thought to result from augmented androgen/androgen receptor (AR) signaling pathway, for most of which AR overexpression has been observed. In this study, Twist1, a member of basic helix-loop-helix transcription factors as well as AR was upregulated in response to hydrogen peroxide, and the response to which was abolished by an addition of N-acetyl-L-cysteine and Twist1 knockdown. In addition, castration-resistant LNCaP derivatives and hydrogen peroxide-resistant LNCaP derivatives exhibited a similar phenotype to each other. Then, both castration and AR knockdown increased intracellular reactive oxygen species level. Moreover, Twist1 was shown to regulate AR expression through binding to E-boxes in AR promoter region. Silencing of Twist1 suppressed cell growth of AR-expressing LNCaP cells as well as castration-resistant LNCaP derivatives by inducing cell-cycle arrest at G1 phase and cellular apoptosis. These findings indicated that castration-induced oxidative stress may promote AR overexpression through Twist1 overexpression, which could result in a gain of castration resistance. Modulation of castration-induced oxidative stress or Twist1/AR signaling might be a useful strategy for developing a novel therapeutics in prostate cancer, even in CRPC, which remains dependent on AR signaling by overexpressing AR.

Original languageEnglish
Pages (from-to)237-250
Number of pages14
JournalOncogene
Volume29
Issue number2
DOIs
Publication statusPublished - Jan 2010

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Cancer Research

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