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Transposon Mediated Integration of Plasmid DNA into the Subventricular Zone of Neonatal Mice to Generate Novel Models of Glioblastoma
Published on: February 22, 2015
Human glioblastoma U87MG cells transduced with a dominant negative p53 (TP53) adenovirus construct undergo
Fiorenza Ianzini1, Frederick E Domann, Elizabeth A Kosmacek
1Department of Pathology, University of Iowa, Iowa City, IA 52242, USA. fiorenza-ianzini@uiowa.edu
Abstract:
Human gliomas are among the most aggressive tumors, and they respond poorly to treatment. The efficacy of surgical, radiation and chemotherapy treatment of these tumors is limited by the development of resistance. Interventions aimed at altering the response of these tumors to radiation or chemotherapy treatments are needed to improve survival rate and prognosis. Glioblastomas are generally p53 (TP53) functional tumors; however, DNA repair pathways are activated in these tumors instead of the pathways to apoptosis. Thus resistance to treatment is seen in the ability of these tumors to overcome cell death. We present data that demonstrate that U87MG glioblastoma cells transduced with a dominant-negative p53 adenovirus construct become sensitized to radiation-induced mitotic catastrophe through abrogation of G(2)/M checkpoint control and overaccumulation of cyclin B1. These findings suggest that interventions abrogating the G(2)/M checkpoint sensitize these cells to radiation-induced mitotic catastrophe and may represent a novel mechanism to increase the efficacy of radiation in wild-type p53 gliomas that are resistant to apoptosis.
Insights
Targeting the G(2)/M checkpoint in glioblastoma sensitizes cells to radiation therapy. This approach may overcome treatment resistance in human gliomas by promoting mitotic catastrophe and apoptosis.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Human gliomas, particularly glioblastomas, are aggressive brain tumors with poor treatment outcomes.
- Treatment resistance, often due to activated DNA repair and apoptosis evasion, limits the efficacy of surgery, radiation, and chemotherapy.
- Glioblastomas typically possess functional p53 (TP53) but activate DNA repair over apoptosis pathways, contributing to treatment resistance.
Purpose of the Study:
- To investigate novel strategies for enhancing radiation therapy efficacy in human gliomas.
- To explore the role of G(2)/M checkpoint control in glioblastoma response to radiation.
- To determine if abrogating the G(2)/M checkpoint sensitizes glioblastoma cells to radiation-induced cell death.
Main Methods:
- U87MG glioblastoma cells were transduced with a dominant-negative p53 adenovirus construct.
- The effect of p53 abrogation on radiation-induced mitotic catastrophe was assessed.
- Changes in G(2)/M checkpoint control and cyclin B1 accumulation were analyzed.
Main Results:
- Transduction with a dominant-negative p53 adenovirus sensitized U87MG glioblastoma cells to radiation.
- Abrogation of the G(2)/M checkpoint led to overaccumulation of cyclin B1.
- These alterations resulted in increased radiation-induced mitotic catastrophe.
Conclusions:
- Abrogating the G(2)/M checkpoint sensitizes glioblastoma cells to radiation-induced mitotic catastrophe.
- This strategy may represent a novel approach to improve radiation therapy efficacy in wild-type p53 gliomas resistant to apoptosis.
- Targeting cell cycle checkpoints offers a potential avenue to overcome treatment resistance in aggressive brain tumors.
