ISL1 promotes enzalutamide resistance in castration-resistant prostate cancer (CRPC) through epithelial to mesenchymal transition (EMT)

Abnormal expression of insulin gene enhancer-binding protein 1 (ISL1) has been demonstrated to be closely associated with cancer development and progression in several cancers. However, little is known about ISL1 expression in metastatic castration-resistant prostate cancer (CRPC). ISL1 has also been recognized as a positive modulator of epithelial-mesenchymal transition (EMT). In this study, we focused on ISL1 which showed maximum upregulation at the mRNA level in the enzalutamide-resistant cell line. Accordingly, we found that ISL1 was overexpressed in enzalutamide-resistant C4-2B cells and its expression was significantly related to EMT. Our findings reveal the important role of ISL1 in androgen receptor (AR)-dependent prostate cancer cell growth; ISL1 knockdown reduced the AR activity and cell growth. ISL1 knockdown using small-interfering RNA inhibited AR, PSA, and EMT-related protein expression in C4-2B ENZR cells. In addition, knock-down ISL1 reduced the levels of AKT and p65 phosphorylation in C4-2B ENZR cells and these suggest that knock-down ISL1 suppresses EMT in part by targeting the AKT/NF-kappa B pathway. Further, ISL1 downregulation could effectively inhibit tumor growth in a human CRPC xenograft model. Together, the present study shows that downregulation of ISL1 expression is necessary for overcoming enzalutamide resistance and improving the survival of CRPC patients.

Automated summary

Abnormal expression of ISL1 has been closely associated with cancer development and progression, with particular focus on its role in the androgen receptor-dependent prostate cancer cell growth, EMT, and enzalutamide resistance. ISL1 knockdown was found to inhibit AR activity, cell growth, and EMT in enzalutamide-resistant cells, suggesting its potential as a therapeutic target for CRPC. The study highlights the importance of downregulating ISL1 expression to overcome enzalutamide resistance and improve survival in CRPC patients.