Abstract
Prostate cancer is the second leading cause of death from cancer among males in Western countries. It is also the most commonly diagnosed male cancer in Japan. The progression of prostate cancer is mainly influenced by androgens and the androgen receptor (AR). Androgen deprivation therapy is an established therapy for advanced prostate cancer; however, prostate cancers frequently develop resistance to low testosterone levels and progress to the fatal stage called castration-resistant prostate cancer (CRPC). Surprisingly, AR and the AR signaling pathway are still activated in most CRPC cases. To overcome this problem, abiraterone acetate and enzalutamide were introduced for the treatment of CRPC. Despite the impact of these drugs on prolonged survival, CRPC acquires further resistance to keep the AR pathway activated. Functional molecular studies have shown that some of the AR collaborative transcription factors (TFs), including octamer transcription factor (OCT1), GATA binding protein 2 (GATA2) and forkhead box A1 (FOXA1), still stimulate AR activity in the castration-resistant state. Therefore, elucidating the crosstalk between the AR and collaborative TFs on the AR pathway is critical for developing new strategies for the treatment of CRPC. Recently, many compounds targeting this pathway have been developed for treating CRPC. In this review, we summarize the AR signaling pathway in terms of AR collaborators and focus on pyrrole-imidazole (PI) polyamide as a candidate compound for the treatment of prostate cancer.
Highlights
Prostate cancer is the major cause of death from cancer among males in Western countries.For example, the American Cancer Society has estimated 180,890 new cases of prostate cancer and26,120 deaths from the disease in the United States in 2016
The androgen receptor (AR) contains an N-terminal domain (NTD; 555 amino acids encoded by exon 1), a DNA-binding domain (DBD; 68 amino acids encoded by exons 2 and 3), a hinge region, and a ligand binding domain (LBD; 295 amino acids encoded by exons 4–8) [25]
We reported that the AR/forkhead box A1 (FOXA1) response gene forkhead box P1 (FOXP1) acts as a negative AR collaborative transcriptional factor, and represses tumor activity by binding to adjacent regions to androgen response elements (AREs) [78,140]
Summary
Prostate cancer is the major cause of death from cancer among males in Western countries. The androgen receptor (AR) signaling pathway plays an integral role in the progression of prostate cancer. Even in a low testosterone environment, AR and its target genes, including prostate-specific antigen (PSA), are still highly expressed in the majority of CRPC lesions [10,11,12]. They activate the cytochrome P450 (CYP) family, which facilitates the unusual conversion of cholesterol to androgen under low testosterone conditions. The study of AR signaling pathways and their collaborative factors will facilitate greater understanding of the mechanisms underlying the progression of advanced prostate cancer as well as the development of novel drugs. This article reviews the AR signaling pathway in CRPC as well as the development of novel therapeutic medicines targeting AR collaborators, especially collaborative DNA binding transcription factors (TFs)
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