Nuclear Receptor LRH-1 Functions to Promote Castration-Resistant Growth of Prostate Cancer via Its Promotion of Intratumoral Androgen Biosynthesis

Abstract

Targeting of steroidogenic enzymes (e.g., abiraterone acetate targeting CYP17A1) has been developed as a novel therapeutic strategy against metastatic castration-resistant prostate cancer (CRPC). However, resistance to steroidal inhibitors inevitably develops in patients, the mechanisms of which remain largely unknown. Liver receptor homolog-1 (LRH-1, ) is a nuclear receptor, originally characterized as an important regulator of some liver-specific metabolic genes. Here, we report that LRH-1, which exhibited an increased expression pattern in high-grade prostate cancer and CRPC xenograft models, functions to promote androgen biosynthesis via its direct transactivation of several key steroidogenic enzyme genes, elevating intratumoral androgen levels and reactivating AR signaling in CRPC xenografts as well as abiraterone-treated CRPC tumors. Pharmacologic inhibition of LRH-1 activity attenuated LRH-1-mediated androgen deprivation and anti-androgen resistance of prostate cancer cells. Our findings not only demonstrate the significant role of LRH-1 in the promotion of intratumoral androgen biosynthesis in CRPC via its direct transcriptional control of steroidogenesis, but also suggest targeting LRH-1 could be a potential therapeutic strategy for CRPC management. These findings not only demonstrate the significant role of the nuclear receptor LRH-1 in the promotion of intratumoral androgen biosynthesis in CRPC via its direct transcriptional control of steroidogenesis, but also suggest targeting LRH-1 could be a potential therapeutic strategy for CRPC management. .

Nuclear receptor HNF4α performs a tumor suppressor function in prostate cancer via its induction of p21-driven cellular senescence

“…PC-3-HNF4α, PC-3-shHNF4α and their empty vectortransduced cells were evaluated of their in vivo tumorigenicity in intact male SCID mice following procedures as described previously [58]. The VCaP-CRPC tumor xenograft model of CRPC was generated as described previously [65,66]. All animal protocols were approved by the CUHK-Animal Experimentation Ethics Committee.…”

Metastatic prostate cancer remains incurable, why?

“…Recently, Xiao et al. [97] found that liver receptor homolog-1 (LRH-1), a nuclear receptor originally characterized as an important regulator of some liver-specific metabolic genes, had a high expression level in CRPC xenograft models. It can promote de novo androgen biosynthesis by its direct transactivation of several key steroidogenic enzyme genes, elevating intratumoral androgen levels and reactivating AR signaling in abiraterone-treated CRPC tumors.…”

Nuclear‐mitochondrial crosstalk: On the role of the nuclear receptor liver receptor homolog‐1 (NR5A2) in the regulation of mitochondrial metabolism, cell survival, and cancer

“…Only recently, in vitro application of SR1848 contributed to the discovery that LRH-1 is also implicated and a possible therapeutic target in castration-resistant prostate cancer (CRPC). 164 This type of cancer is typically associated with persistent androgen receptor (AR) signaling caused by the constant biosynthesis of intratumoral androgens and thus commonly treated with steroidal inhibitors. 165 Xiao et al were able to show that LRH-1 is not only upregulated in CRPC tissue, but also promoting growth and androgen production of prostate cancer cells in vivo.…”