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Int. J. Mol. Sci. 2017, 18(6), 1130; doi:10.3390/ijms18061130

Melatonin Inhibits Androgen Receptor Splice Variant-7 (AR-V7)-Induced Nuclear Factor-Kappa B (NF-κB) Activation and NF-κB Activator-Induced AR-V7 Expression in Prostate Cancer Cells: Potential Implications for the Use of Melatonin in Castration-Resistant Prostate Cancer (CRPC) Therapy

1
School of Biomedical Sciences, The University of Hong Kong, Hong Kong, China
2
Division of Nursing and Health Studies, School of Science and Technology, Open University of Hong Kong, Hong Kong, China
*
Author to whom correspondence should be addressed.
Academic Editor: Russel J. Reiter
Received: 28 March 2017 / Revised: 9 May 2017 / Accepted: 17 May 2017 / Published: 31 May 2017
(This article belongs to the Special Issue Melatonin and Its Analogues: Experimental and Clinical Aspects)
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Abstract

A major current challenge in the treatment of advanced prostate cancer, which can be initially controlled by medical or surgical castration, is the development of effective, safe, and affordable therapies against progression of the disease to the stage of castration resistance. Here, we showed that in LNCaP and 22Rv1 prostate cancer cells transiently overexpressing androgen receptor splice variant-7 (AR-V7), nuclear factor-kappa B (NF-κB) was activated and could result in up-regulated interleukin (IL)-6 gene expression, indicating a positive interaction between AR-V7 expression and activated NF-κB/IL-6 signaling in castration-resistant prostate cancer (CRPC) pathogenesis. Importantly, both AR-V7-induced NF-κB activation and IL-6 gene transcription in LNCaP and 22Rv1 cells could be inhibited by melatonin. Furthermore, stimulation of AR-V7 mRNA expression in LNCaP cells by betulinic acid, a pharmacological NF-κB activator, was reduced by melatonin treatment. Our data support the presence of bi-directional positive interactions between AR-V7 expression and NF-κB activation in CRPC pathogenesis. Of note, melatonin, by inhibiting NF-κB activation via the previously-reported MT1 receptor-mediated antiproliferative pathway, can disrupt these bi-directional positive interactions between AR-V7 and NF-κB and thereby delay the development of castration resistance in advanced prostate cancer. Apparently, this therapeutic potential of melatonin in advanced prostate cancer/CRPC management is worth translation in the clinic via combined androgen depletion and melatonin repletion. View Full-Text
Keywords: melatonin; androgen receptor splice variant-7; nuclear factor-kappa B; castration-resistant prostate cancer melatonin; androgen receptor splice variant-7; nuclear factor-kappa B; castration-resistant prostate cancer
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Liu, V.W.S.; Yau, W.L.; Tam, C.W.; Yao, K.-M.; Shiu, S.Y.W. Melatonin Inhibits Androgen Receptor Splice Variant-7 (AR-V7)-Induced Nuclear Factor-Kappa B (NF-κB) Activation and NF-κB Activator-Induced AR-V7 Expression in Prostate Cancer Cells: Potential Implications for the Use of Melatonin in Castration-Resistant Prostate Cancer (CRPC) Therapy. Int. J. Mol. Sci. 2017, 18, 1130.

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