Abstract
Prostate cancer (PCa) is the most common cancer amongst men. A novel androgen receptor (AR) antagonist, enzalutamide (ENZA) has recently been demonstrated to enhance the effect of radiation (XRT) by impairing the DNA damage repair process. This study aimed to identify a radiosensitive gene signature induced by ENZA in the PCa cells and to elucidate the biological pathways which influence this radiosensitivity. We treated LNCaP (AR-positive, hormone-sensitive PCa cells) and C4-2 (AR-positive, hormone-resistant PCa cells) cells with ENZA alone and in combination with androgen deprivation therapy (ADT) and XRT. Using one-way ANOVA on the gene expression profiling, we observed significantly differentially expressed (DE) genes in inflammation-and metabolism-related genes in hormone-sensitive and hormone-resistant PCa cell lines respectively. Survival analysis in both the TCGA PRAD and GSE25136 datasets suggested an association between the expression of these genes and time to recurrence. These results indicated that ENZA alone or in combination with ADT enhanced the effect of XRT through immune and inflammation-related pathways in LNCaP cells and metabolic-related pathways in C4-2 cells. Kaplan–Meier analysis and Cox proportional hazard models showed that low expression of all the candidate genes except for PTPRN2 were associated with tumor progression and recurrence in a PCa cohort.
Highlights
Of Prostate cancer (PCa) with a median survival rate of fewer than two years[8]
We have demonstrated that ENZA with or without androgen deprivation therapy (ADT) enhances the effect of XRT in both hormone-sensitive (LNCaP) and hormone-resistant (C4-2) PCa cell lines[10]
To identify radiosensitivity gene signatures and elucidate related signalling pathways, we performed gene expression analysis on the cells treated with XRT or ENZA ± ADT in combination with XRT
Summary
Of PCa with a median survival rate of fewer than two years[8]. ENZA targets the AR signalling pathway at three key stages: (1) It blocks binding of androgens to the AR; (2) It prevents AR nuclear translocation within the nucleus; (3) It inhibits binding of activated AR to chromosomal DNA, which prevents transcription of target genes[9]. The aim of our research is to identify the radiosensitivity gene signature(s) induced by ENZA in PCa cells and to clarify the biological pathways that play important roles in the regulation of radiosensitivity. While radiation induces cell death through DNA damage, there are no clinically predictive markers available to indicate the likelihood of an effective treatment outcome[11]. In order to identify a common radiosensitivity gene signature and relevant biological pathways, we carried out gene expression profiling following treatment of LNCaP and C4-2 cell lines. We hypothesized that these gene signatures play a role in the radiosensitivity of PCa cell lines in different combined treatment modalities
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