beta Arrestin1 regulates glucocorticoid receptor mitogenic signaling in castration-resistant prostate cancer
PROSTATE(2022)
摘要
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 methods that inhibit androgen receptor (AR) signal transduction. Laboratory-based and clinical studies have identified alternative pathways that cause the failure of AR signal inhibition and consequent development of castration-resistant prostate cancer (CRPC). Glucocorticoid receptor (GR) signaling is activated in certain PC patients and promotes the emergence of CRPC, although by as yet incompletely understood mechanisms. We have previously demonstrated that ubiquitous beta arrestin1. (beta Arr1) expression levels are linked to PC progression. Here, we consider the possibility that beta Arr1 interacts with and activates GR in model CRPC cells. Methods: Bioinformatic analysis of tumor xenograft and human PC datasets was used to correlate the expression of beta Arr1 and GR. Western blot, immunohistochemistry and immunofluorescence microscopy, and subcellular fractionation were used to determine protein expression level and localization. lmmunoprecipitation 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 beta Arr1 positively correlated with increased GR expression and function in CRPC xenograft and in human PC patients. beta Arr1 is expressed in the cell cytosol and nucleus, and it formed a complex with GR in the nucleus and not cytosol. Depletion of beta Arr1 in AR-null CRPC cells inhibited GR function and CRPC growth and invasion in both in vitro and in vivo settings. Conclusions: beta Arr1. binds GR that initiates mitogenic signaling cascades involved in the progression of PC to CRPC. The targeting of the beta Arr1-GR axis may provide a new opportunity to better manage the CRPC disease.
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关键词
castration-resistant prostate cancer, glucocorticoid receptor coactivator, metastasis, prostate cancer progression, tumorigenesis, beta arrestin1
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