Enzalutamide effectively inhibits the growth of meningiomas via p21-dependent senescence induction.

BACKGROUND

Meningiomas are the most common central nervous system tumors and are primarily managed through surgical resection and radiation therapy. The development of meningioma is associated with sex steroid hormone-related risk factors. However, anti-sex steroid hormone therapy in meningiomas is still unclear.

METHODS

Expression levels of sex steroid hormone receptors were determined in meningioma tissues and cell lines via quantitative PCR. The effects of androgen receptor inhibitor (enzalutamide; ENZ) on meningioma cell growth were investigated via cell viability test, cell cycle analysis and senescence-associated β-galactosidase activity.

RESULTS

Androgen receptor (AR) expression was observed in all WHO grade meningiomas. In comparison, progesterone receptor (PR) expression was detected mainly in WHO grade 1 meningiomas but was absent in grade 3 meningiomas. Targeting AR with ENZ significantly inhibited the growth of malignant meningioma cells (HKBMM and IOMM-Lee). Malignant meningioma cells, particularly IOMM-Lee cells, were sensitive to ENZ. ENZ induced cell cycle arrest and increased the sub-G1 population in both malignant meningioma cell lines. Elevated cyclin D1 expression and loss of replicative potential via the reduction of Ki-67 nuclei were also observed. ENZ induced senescence-associated β-galactosidase activity, associated with up-regulation of p21 and down-regulation of the anti-apoptotic protein Mcl-1, in both malignant meningioma cell lines. Additionally, down-regulation of AR-positive cells and AR target genes, including EDN2, TMPRSS2, and KLK3, was observed only in HKBMM cells expressing AR.

CONCLUSIONS

Our findings suggest that ENZ induces a senescence-like phenotype in malignant meningioma cells via p21-dependent induction. Lastly, ENZ may serve as a promising targeted therapy for meningiomas, particularly for aggressive subtypes or in cases of recurrence.