Nuclear receptor NR5A2 negatively regulates cell proliferation and tumor growth in nervous system malignancies
Menée in vitro et à l'aide de xénogreffes de tumeurs du système nerveux (neuroblastome, glioblastome) sur des modèles murins, cette étude met en évidence un mécanisme par lequel le récepteur nucléaire NR5A2 inhibe la prolifération cellulaire et la croissance tumorale
Résumé en anglais
Glioblastomas and neuroblastomas are aggressive cancer types with poor prognosis. Identification of druggable factors that inhibit these tumors will contribute to new therapies. Our data show that nuclear receptor NR5A2 suppresses the growth of glioblastomas and neuroblastomas. This function is facilitated by the ability of NR5A2 to induce critical cell cycle inhibitors including p21, p27, and Prox1. Two small molecule agonists of NR5A2, dilauroyl phosphatidylcholine, and diundecanoyl phosphatidylcholine can mimic its antitumor effect. Our results identify NR5A2 as a potential drug target in nervous system–related cancers.Nervous system malignancies are characterized by rapid progression and poor survival rates. These clinical observations underscore the need for novel therapeutic insights and pharmacological targets. To this end, here, we identify the orphan nuclear receptor NR5A2/LRH1 as a negative regulator of cancer cell proliferation and promising pharmacological target for nervous system–related tumors. In particular, clinical data from publicly available databases suggest that high expression levels of NR5A2 are associated with favorable prognosis in patients with glioblastoma and neuroblastoma tumors. Consistently, we experimentally show that NR5A2 is sufficient to strongly suppress proliferation of both human and mouse glioblastoma and neuroblastoma cells without inducing apoptosis. Moreover, short hairpin RNA–mediated knockdown of the basal expression levels of NR5A2 in glioblastoma cells promotes their cell cycle progression. The antiproliferative effect of NR5A2 is mediated by the transcriptional induction of negative regulators of the cell cycle, CDKN1A (encoding for p21cip1), CDKN1B (encoding for p27kip1) and Prox1. Interestingly, two well-established agonists of NR5A2, dilauroyl phosphatidylcholine (DLPC) and diundecanoyl phosphatidylcholine, are able to mimic the antiproliferative action of NR5A2 in human glioblastoma cells via the induction of the same critical genes. Most importantly, treatment with DLPC inhibits glioblastoma tumor growth in vivo in heterotopic and orthotopic xenograft mouse models. These data indicate a tumor suppressor role of NR5A2 in the nervous system and render this nuclear receptor a potential pharmacological target for the treatment of nervous tissue–related tumors.All study data are included in the article and/or the SI Appendix.
