Cbio-31. Sex Differences in the Activity of Cyclin Dependent Kinase Inhibitors Underlie Greater Threshold for Gliomic Transformation in Female Astrocytes
Year: 2017
Type: conference-abstract
Abstract: Sex differences in cancer incidence are pervasive regardless of age or race. However, the molecular mechanisms underlying these differences remain undefined. Previously, we showed that sex differences in the regulation of retinoblastoma protein (Rb) function has been shown to correlate with differential vulnerability to malignant transformation to mesenchymal glioblastoma (mes-GBM) in male and female cortical astrocytes lacking functional neurofibromin and p53. We hypothesized that these sex differences in susceptibility to transformation may be driven by the differential activities of cyclin dependent kinase inhibitors. We found that p16 and p21, but not p27 exhibited sexually dimorphic activity corresponding to sex differences cell cycle arrest and transformation. In response to serum deprivation and DNA damage, female mes-GBM astrocytes increase p16 and p21 expression respectively, leading to cell cycle arrest. In contrast, male mes-GBM astrocytes continue to proliferate, acquire chromosomal aberrations, and display greater clonogenic cell frequency and in vivo tumorigenesis. Abrogation of p16 and p21 activity in female mes-GBM astrocytes mitigates these phenotypic differences. An analysis of pharmacological CDK inhibition revealed that the sex differences in p16 and p21 activity are correlated with sex differences in response to CDK4/6 and CDK5-CDK2 pathway inhibitors. These data provide new evidence for sex differences in growth regulation and transformation and suggest that these differences can render male and female cells differentially sensitive to targeted therapeutics. Finally, they indicate that sex differences should be considered in the investigation of novel cancer therapeutics in both the lab and clinical setting.
Source: Neuro-Oncology
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2767937415