ROCK inhibition reduces the sensitivity of mutant p53 glioblastoma to genotoxic stress through a Rac1-driven ROS
Yuli Thamires Magalhaes1, Fabio Luis Forti1
1Laboratory of Signaling in Biomolecular Systems, Department of Biochemistry, Institute of Chemistry, University of São Paulo, São Paulo, Brazil.
The International Journal of Biochemistry & Cell Biology
|October 1, 2023
Summary
Rho-associated kinase inhibitors modulate glioblastoma response to genotoxic treatments by affecting DNA repair pathways differently in cells with wild-type versus mutant p53. This suggests p53 status is a key determinant for glioblastoma therapy.
Area of Science:
- Molecular Biology
- Cancer Research
- Neuro-oncology
Background:
- Glioblastoma (GBM) exhibits resistance to radio and chemotherapy, linked to its malignancy and invasiveness.
- The Rho GTPase pathway is implicated in GBM aggressiveness, but its role in treatment response is unclear.
- Pharmacological inhibition of Rho-associated kinases (ROCK) is a potential therapeutic strategy for CNS diseases.
Purpose of the Study:
- To investigate the role of ROCK inhibition in GBM cell response to genotoxic stress (gamma ionizing radiation and cisplatin).
- To determine if p53 status (wild-type vs. mutant) influences the effects of ROCK inhibition on GBM cells.
- To elucidate the DNA repair mechanisms modulated by ROCK inhibition in a p53-dependent manner.
Main Methods:
- Pharmacological inhibition of ROCK using Y-27632 in GBM cells with wild-type or mutant p53.
- Exposure of cells to genotoxic stress induced by gamma ionizing radiation (IR) or cisplatin (PT).
- Assessment of cell survival, DNA repair capacity (γH2AX foci, strand breaks), reactive oxygen species (ROS) production, and specific DNA repair pathway activity (NHEJ, NER, HR).
Main Results:
- ROCK inhibition reduced survival and DNA repair in wild-type p53 GBM cells, attenuating NHEJ and NER pathways.
- ROCK inhibition enhanced survival and DNA repair in mutant p53 GBM cells by stimulating HR and NER pathways.
- Genotoxic stress induced ROS in mutant p53 cells, potentiated by ROCK inhibition, and dependent on Rac1 activity.
Conclusions:
- ROCK inhibition differentially modulates GBM sensitivity and resistance to genotoxic agents based on p53 status.
- Targeting ROCK inhibitors in combination with radio/chemotherapy could be a strategy to overcome GBM resistance.
- p53 activity is a critical factor in predicting response to combined therapies, highlighting its potential as a therapeutic target for pre-sensitization.
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