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.
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Acknowledgements
This work was supported in part by Health Sciences Research Grants for Clinical Research for evidence-based medicine and grants-in-aid for Cancer Research (016), from the Ministry of Health, Labor and Welfare, Japan, Young Researcher Promotion Grant from the Japanese Urological Association, Japan. We are grateful to Dr Chawnshang Chang for providing the pCMV-AR plasmid. We would like to thank Dr Dongchon Kang (Kyushu University, Fukuoka, Japan) for helping with quantitative real-time PCR and flow cytometry, and Noriko Hakoda, Hitomi Matoba and Seiko Kamori for their technical assistances.
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Shiota, M., Yokomizo, A., Tada, Y. et al. Castration resistance of prostate cancer cells caused by castration-induced oxidative stress through Twist1 and androgen receptor overexpression. Oncogene 29, 237–250 (2010). https://doi.org/10.1038/onc.2009.322
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DOI: https://doi.org/10.1038/onc.2009.322
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