PLCε knockdown enhances the radiosensitivity of castration‑resistant prostate cancer via the AR/PARP1/DNA‑PKcs axis

Abstract

Radiotherapy (RT) has been used as a therapeutic option for treatment of prostate cancer (PCa) for a number of years; however, patients frequently develop RT resistance, particularly in castration-resistant PCa (CRPC), although the underlying mechanisms remain unknown. Understanding the underlying mechanism of RT resistance in CRPC may potentially highlight novel targets to improve therapeutic options for patients with PCa. In the present study, the expression levels of phospholipase Cε (PLCε), androgen receptor (AR) and DNA-dependent protein kinase catalytic subunit (PKcs) were examined in PCa tissue samples and PCa cells, and the effects of PLCε knockdown on AR and DNA damage repair (DDR)-related molecules were determined. The association between PLCε, AR and Poly (ADP-ribose) polymerase 1 (PARP1), as well as their respective roles in radiation resistance, were assessed using gene knockdown and pharmaceutical inhibitors or activators. A chromatin immunoprecipitation assay was used to determine the epigenetic regulatory effects of PLCε on PARP1. Animal experiments were performed to assess whether the mechanisms observed in vitro could be replicated in vivo. The expression levels of PLCε, AR and DNA-PKcs were significantly upregulated in PCa, particularly in CRPC. PLCε knockdown reduced the viability and increased apoptosis of cells subjected to radiation. Additionally, PLCε deficiency suppressed DDR progression by downregulating an AR and PARP1 positive feedback loop and the associated downstream molecules following radiation. PLCε depletion also increased the presence of histone H3 lysine 27 trimethylation in the PARP1 promoter region, suggesting increased methylation of the PARP1 gene and thus resulting in reduced expression of PARP1. In vivo, PLCε knockdown significantly potentiated the effects of radiation on tumor growth. Taken together, the results of the present study demonstrated that PLCε knockdown enhanced the radiosensitivity of CRPC by downregulating the AR/PARP1/DNA-PKcs axis.

Recent Research Advances in Double-Strand Break and Mismatch Repair Defects in Prostate Cancer and Potential Clinical Applications

“…The dysregulation of the DNA-PKcs has been implicated in PC progression, metastasis, and resistance to therapy, and its upregulation correlates with poor patient outcomes [60,137,138]. In a study by Pu J. et al, it was suggested that the downregulation of the Androgen receptor/PARP/DNA-PKcs axis could be used as a potential therapeutic strategy to increase the radiosensitivity of castrate-resistant PCs [139].…”

Drug Repurposing of Pantoprazole and Vitamin C Targeting Tumor Microenvironment Conditions Improves Anticancer Effect in Metastatic Castration-Resistant Prostate Cancer

“…In early stage, when the disease is limited to the prostate, surgical and/or medical castration is the most preferred therapy, but more than 90% of patients develop castration-resistant prostate cancer (CRPC) ( 1 ). Although, radiotherapy is an alternative therapeutic choice for patients with CRPC ( 3 ), the relapse presented following radiation therapy in 30–50% patients still ( 4 , 5 ).One new and very effective strategy involves the administration of radio-ligands that target prostate-specific membrane antigen (PSMA), which is overexpressed in prostate cancer cells. For this purpose, both the beta-emitter Lu-177 and the alpha-emitter Ac-225 are coupled to PSMA-617 or PSMA-I&T targeting metastatic prostate cancer cells ( 6 , 7 ).However, these therapies are not promoted by the China Food and Drug Administration (CFDA).…”