Castration resistance of prostate cancer cells caused by castration-induced oxidative stress through Twist1 and androgen receptor overexpression.
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.
Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
M
M
Shiota
A
A
Yokomizo
Y
Y
Tada
J
J
Inokuchi
E
E
Kashiwagi
D
D
Masubuchi
M
M
Eto
T
T
Uchiumi
S
S
Naito
D000111:Acetylcysteine / Q000494:pharmacology; D017209:Apoptosis; D001665:Binding Sites; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019008:Drug Resistance, Neoplasm; D016166:Free Radical Scavengers / Q000494:pharmacology; D016193:G1 Phase; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008297:Male; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D009919:Orchiectomy; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress; D011401:Promoter Regions, Genetic / Q000235:genetics; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D034622:RNA Interference; D011944:Receptors, Androgen / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051879:Twist-Related Protein 1 / Q000235:genetics* / Q000378:metabolism
D016166:Free Radical Scavengers; D009687:Nuclear Proteins; D016877:Oxidants; D011944:Receptors, Androgen; C103173:TWIST1 protein, human; D051879:Twist-Related Protein 1; D006861:Hydrogen Peroxide; D000111:Acetylcysteine