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
Open Access
- 31 May 2017
- journal article
- research article
- Published by MDPI AG in International Journal of Molecular Sciences
- Vol. 18 (6), 1130
- https://doi.org/10.3390/ijms18061130
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.This publication has 37 references indexed in Scilit:
- Increased Survival with Enzalutamide in Prostate Cancer after ChemotherapyThe New England Journal of Medicine, 2012
- Resistance to CYP17A1 Inhibition with Abiraterone in Castration-Resistant Prostate Cancer: Induction of Steroidogenesis and Androgen Receptor Splice VariantsClinical Cancer Research, 2011
- A snapshot of the expression signature of androgen receptor splicing variants and their distinctive transcriptional activitiesThe Prostate, 2011
- Castration resistance in human prostate cancer is conferred by a frequently occurring androgen receptor splice variantJCI Insight, 2010
- Anti-androgens and androgen-depleting therapies in prostate cancer: new agents for an established targetThe Lancet Oncology, 2009
- Selective Inhibition of CYP17 With Abiraterone Acetate Is Highly Active in the Treatment of Castration-Resistant Prostate CancerJournal of Clinical Oncology, 2009
- Development of a Second-Generation Antiandrogen for Treatment of Advanced Prostate CancerScience, 2009
- A Novel Androgen Receptor Splice Variant Is Up-regulated during Prostate Cancer Progression and Promotes Androgen Depletion–Resistant GrowthCancer Research, 2009
- Ligand-Independent Androgen Receptor Variants Derived from Splicing of Cryptic Exons Signify Hormone-Refractory Prostate CancerCancer Research, 2008
- Targeting the androgen receptor pathway in prostate cancerCurrent Opinion in Pharmacology, 2008