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.
Subject(s)
Gene Expression Regulation, Neoplastic/genetics , Melatonin/pharmacology , NF-kappa B/metabolism , Receptors, Androgen/genetics , Alternative Splicing , Antineoplastic Agents, Phytogenic/pharmacology , Antioxidants/pharmacology , Cell Line, Tumor , Gene Expression Regulation, Neoplastic/drug effects , Humans , Male , NF-kappa B/antagonists & inhibitors , Pentacyclic Triterpenes , Prostatic Neoplasms/genetics , Prostatic Neoplasms/metabolism , Prostatic Neoplasms/pathology , Prostatic Neoplasms, Castration-Resistant/genetics , Prostatic Neoplasms, Castration-Resistant/metabolism , Prostatic Neoplasms, Castration-Resistant/pathology , Protein Isoforms/genetics , Protein Isoforms/metabolism , Receptors, Androgen/metabolism , Triterpenes/pharmacology , Tryptamines/pharmacology , Betulinic AcidABSTRACT
Tumor suppressive actions of the autocrine human secreted PDZ domain-containing protein 2 (sPDZD2) have been reported, but the mechanisms remain enigmatic. Here, we showed that sPDZD2 induced senescence of prostate cancer DU145 cells, quiescence of breast cancer MCF-7 and liver cancer Hep-G2 cells, via transcriptional activation of mutant or wild-type p53. Furthermore, sPDZD2 sensitized mutant p53-positive DU145 cells and wild-type p53-positive MCF-7 cells to apoptosis induction through genotoxic stress imposed by sub-lethal concentration of hydrogen peroxide. Together, our findings suggest a potential autocrine pathway of p53 activation by transcriptional regulation, and a new approach to reactivate p53 for cancer therapy.
