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Cooperative p16 and p21 action protects female astrocytes from transformation

Najla Kfoury¹, Tao Sun¹, Kwanha Yu²

¹Department of Pediatrics, Washington University School of Medicine, Campus Box 8208, 660 South Euclid Ave, St Louis, MO, 63110, USA.

Acta Neuropathologica Communications

|February 21, 2018

Abstract:

Mechanisms underlying sex differences in cancer incidence are not defined but likely involve dimorphism (s) in tumor suppressor function at the cellular and organismal levels. As an example, sexual dimorphism in retinoblastoma protein (Rb) activity was shown to block transformation of female, but not male, murine astrocytes in which neurofibromin and p53 function was abrogated (GBM astrocytes). Correlated sex differences in gene expression in the murine GBM astrocytes were found to be highly concordant with sex differences in gene expression in male and female GBM patients, including in the expression of components of the Rb and p53 pathways. To define the basis of this phenomenon, we examined the functions of the cyclin dependent kinase (CDK) inhibitors, p16, p21 and p27 in murine GBM astrocytes under conditions that promote Rb-dependent growth arrest. We found that upon serum deprivation or etoposide-induced DNA damage, female, but not male GBM astrocytes, respond with increased p16 and p21 activity, and cell cycle arrest. In contrast, male GBM astrocytes continue to proliferate, accumulate chromosomal aberrations, exhibit enhanced clonogenic cell activity and in vivo tumorigenesis; all manifestations of broad sex differences in cell cycle regulation and DNA repair. Differences in tumorigenesis disappeared when female GBM astrocytes are also rendered null for p16 and p21. These data elucidate mechanisms underlying sex differences in cancer incidence and demonstrate sex-specific effects of cytotoxic and targeted therapeutics. This has critical implications for lab and clinical research.

Insights

Sex differences in cancer incidence are linked to varying tumor suppressor activity. Female astrocytes resist cancer via p16 and p21, while males do not, impacting cell cycle regulation and DNA repair.

Area of Science:

Oncology
Cell Biology
Genetics

Background:

Mechanisms driving sex differences in cancer incidence remain unclear.
Sexual dimorphism in tumor suppressor function, such as retinoblastoma protein (Rb) activity, is implicated.
Previous studies show sex differences in gene expression in murine and human glioblastoma (GBM) astrocytes.

Purpose of the Study:

To investigate the role of cyclin-dependent kinase (CDK) inhibitors (p16, p21, p27) in sex differences in GBM astrocyte proliferation and cell cycle regulation.
To elucidate the molecular basis for sex-specific differences in cancer incidence and response to DNA damage.

Main Methods:

Utilized murine glioblastoma (GBM) astrocytes with abrogated neurofibromin and p53 function.
Examined the activity of p16, p21, and p27 under conditions promoting Rb-dependent growth arrest (serum deprivation, etoposide treatment).
Assessed cell cycle arrest, chromosomal aberrations, clonogenic activity, and in vivo tumorigenesis.

Main Results:

Female GBM astrocytes exhibited increased p16 and p21 activity, leading to cell cycle arrest upon DNA damage or serum deprivation.
Male GBM astrocytes continued to proliferate, accumulating aberrations and demonstrating enhanced tumorigenesis.
Loss of p16 and p21 in female GBM astrocytes abolished these sex differences in tumorigenesis.

Conclusions:

p16 and p21 activity mediate sex differences in cell cycle regulation and DNA repair in GBM astrocytes.
These findings reveal mechanisms underlying sex disparities in cancer incidence.
Demonstrates sex-specific effects of therapeutics, with critical implications for research and clinical practice.

Read full analysis

Keywords:

Cyclin dependent kinase inhibitors DNA damage response Glioblastoma Glioma Rb Sex differences p16 p21

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