Gonadal sex patterns p21-induced cellular senescence in mouse and human glioblastoma

Males exhibit higher incidence and worse prognosis for the majority of cancers, including glioblastoma (GBM). Disparate survival may be related to sex-biased responses to treatment, including radiation. Using a mouse model of GBM, we show that female cells are more sensitive to radiation, and that senescence represents a major component of the radiation therapeutic response in both sexes. Correlation analyses revealed that the CDK inhibitor p21 and irradiation induced senescence were differentially regulated between male and female cells. Indeed, female cellular senescence was more sensitive to changes in p21 levels, a finding that was observed in wildtype and transformed murine astrocytes, as well as patient-derived GBM cell lines. Using a novel Four Core Genotypes model of GBM, we further show that sex differences in p21-induced senescence are patterned during early development by gonadal sex. These data provide a rationale for the further study of sex differences in radiation response and how senescence might be enhanced for radiation sensitization. The determination that p21 and gonadal sex are required for sex differences in radiation response will serve as a foundation for these future mechanistic studies. In human and murine GBM cells, and wildtype murine astrocytes, radiation induces senescence. Overall, female cells are more sensitive to radiation and to p21-induced senescence. This may contribute to the female survival advantage in GBM.

Automated summary

Males have higher incidence and worse prognosis for most cancers, including glioblastoma (GBM). The study shows that female cells are more sensitive to radiation and senescence plays a major role in radiation therapeutic response in both sexes. Differences in CDK inhibitor p21 and irradiation-induced senescence regulation between male and female cells were observed. The findings suggest that exploring sex differences in radiation response and enhancing senescence for radiation sensitization could be beneficial.