ATM-JAK-PD-L1 signaling pathway inhibition decreases EMT and metastasis of androgen-independent prostate cancer

摘要

Castration-resistant prostate cancer (CRPC), also known as androgen-independent prostate cancer, frequently develops local and distant metastases, the underlying mechanisms of which remain undetermined. In the present study, surgical specimens obtained from patients with clinical prostate cancer were investigated, and it was revealed that the expression levels of ataxia telangiectasia mutated kinase (ATM) were significantly enhanced in prostate cancer tissues isolated from patients with CRPC compared with from patients with hormone-dependent prostate cancer. CRPC C4-2 and CWR22Rv1 cells lines were subsequently selected to establish prostate cancer models, and ATM knockout cells were established via lentivirus infection. The results of the present study demonstrated that the migration and epithelial-mesenchymal transition (EMT) of ATM knockout cells were significantly decreased, which suggested that ATM is closely associated with CRPC cell migration and EMT. To further investigate the mechanisms underlying this process, programmed cell death 1 ligand 1 (PD-L1) expression was investigated in ATM knockout cells. In addition, inhibitors of Janus kinase (JAK) and signal transducer and activator of transcription 3 (STAT3; Stattic) were added to C4-2-Sc and CWR22Rv1-Sc cells, and the results demonstrated that PD-L1 expression was significantly decreased following the addition of JAK inhibitor 1; however, no significant change was observed following the addition of Stattic. Furthermore, a PD-L1 antibody and JAK inhibitor 1 were added to C4-2-Sc and CWR22Rv1-Sc cells, and it was revealed that cell migration ability was significantly decreased and the expression of EMT-associated markers was effectively reversed. The results of the present study suggested that via inhibition of the ATM-JAK-PD-L1 signaling pathway, EMT, metastasis and progression of CRPC may be effectively suppressed, which may represent a novel therapeutic approach for targeted therapy for patients with CRPC.