TY - JOUR
T1 - Cooperative p16 and p21 action protects female astrocytes from transformation
AU - Kfoury, Najla
AU - Sun, Tao
AU - Yu, Kwanha
AU - Rockwell, Nathan
AU - Tinkum, Kelsey L.
AU - Qi, Zongtai
AU - Warrington, Nicole M.
AU - McDonald, Peter
AU - Roy, Anuradha
AU - Weir, Scott J.
AU - Mohila, Carrie A.
AU - Deneen, Benjamin
AU - Rubin, Joshua B.
N1 - Funding Information:
The authors would like to thank Dr. Robi D. Mitra for his assistance with statistical analysis. This work was supported by NIH RO1 CA174737 (JBR), Joshua’s Great Things (JBR), Sontag Foundation (BD), Cancer prevention Research Institute of Texas (RP510334 and RP160192 to BD), KUMC cancer center grant support (5P30CA168524-02) and the American Cancer Society (KU). The High Throughput Screening Laboratory at the University of Kansas is supported by the NCI Cancer Center Support Grant P30 CA168524 and NIH COBRE grant P20 GM113117. The Siteman Flow Cytometry Core is supported in part by an NCI Cancer Center Support Grant #P30 CA91842. The Genome Technology Access Center in the Department of Genetics at Washington University School of Medicine is partially supported by NCI Cancer Center Support Grant #P30 CA91842 and by ICTS/CTSA Grant# UL1 TR000448 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research. This publication is solely the responsibility of the authors and does not necessarily represent the official view of NCRR or NIH.
PY - 2018/2/20
Y1 - 2018/2/20
N2 - 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.
AB - 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.
KW - Cyclin dependent kinase inhibitors
KW - DNA damage response
KW - Glioblastoma
KW - Glioma
KW - Rb
KW - Sex differences
KW - p16
KW - p21
UR - http://www.scopus.com/inward/record.url?scp=85051689918&partnerID=8YFLogxK
U2 - 10.1186/s40478-018-0513-5
DO - 10.1186/s40478-018-0513-5
M3 - Article
C2 - 29458417
AN - SCOPUS:85051689918
SN - 2051-5960
VL - 6
SP - 12
JO - Acta Neuropathologica Communications
JF - Acta Neuropathologica Communications
IS - 1
ER -