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

Seong Il Seo,Seong Soo Jeon,Jae Duck Choi,Seon Yong Yeom,Min Yong Kang,Tae Jin Kim,Byong Chang Jeong,Hwang Gyun Jeon

doi:10.1038/s41598-021-01003-0

Abstract

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-κB 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.

Highlights

Androgen deprivation therapy (ADT) is the mainstay treatment for advanced prostate cancer (PCa), given the importance of androgens for PCa development
As the tumor sphere formation is based on the unique property of stem/progenitor cells to survive and grow in a serum-free medium, we performed a tumor sphere formation assay to examine whether enzalutamide resistance enhances the self-renewal of PCa cells
We demonstrate that the downregulation of Insulin gene enhancer-binding protein 1 (ISL1) serves as an important alternative therapy for castration-resistant prostate cancer (CRPC) treatment through the targeting of Epithelial–mesenchymal transition (EMT) via the negative regulation of the AKT/NF-κB signaling pathway

Summary

Introduction

Androgen deprivation therapy (ADT) is the mainstay treatment for advanced prostate cancer (PCa), given the importance of androgens for PCa development. Epithelial–mesenchymal transition (EMT) is a process by which epithelial cells undergo morphological changes to acquire a motile mesenchymal phenotype. This phenomenon is implicated in cancer metastasis and in the development of therapeutic resistance[10,11]. ISL1 may act as a positive modulator of EMT, a critical regulator of cancer stem cell (CSC) phenotype. This is especially important as CSCs are a subpopulation of neoplastic cells with stem cell-like properties such as the ability to self-renew and undergo metastasis[19,20,21]. The molecular basis underlying these effects is not well understood, and to the best of our knowledge, has not been investigated in the context of PCa

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Results

Conclusion