Background
Prostate cancer (PC) is the most commonly diagnosed malignancy and the second leading cause of cancer-related deaths in males. The disease is initially treated with
Conclusions
βArr1 binds GR that initiates mitogenic signaling cascades involved in the progression of PC to CRPC. The targeting of the βArr1-GR axis may provide a new opportunity to better manage the CRPC disease.
Methods
Bioinformatic analysis of tumor xenograft and human PC datasets was used to correlate the expression of βArr1 and GR. Western blot, immunohistochemistry and immunofluorescence microscopy, and subcellular fractionation were used to determine protein expression level and localization. Immunoprecipitation was applied to detect protein-protein interactions. RNA expression levels were determined using quantitative reverse transcription-polymerase chain reaction. Prostate sphere analysis was used to assess the rate of growth and invasion. The xenograft tumor implantation method was used to determine the tumor growth rate, local invasion, and metastasis.
Results
Elevated expression of βArr1 positively correlated with increased GR expression and function in CRPC xenograft and in human PC patients. βArr1 is expressed in the cell cytosol and nucleus, and it formed a complex with GR in the nucleus and not cytosol. Depletion of βArr1 in AR-null CRPC cells inhibited GR function and CRPC growth and invasion in both in vitro and in vivo settings. Conclusions: βArr1 binds GR that initiates mitogenic signaling cascades involved in the progression of PC to CRPC. The targeting of the βArr1-GR axis may provide a new opportunity to better manage the CRPC disease.