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Intracellular Redox-Balance Involvement in Temozolomide Resistance-Related Molecular Mechanisms in Glioblastoma
Alessia Lo Dico1, Daniela Salvatore2,3, Cristina Martelli4
1Department of Pathophysiology and Transplantation, University of Milan, 20090 Segrate (MI), Italy. alessia.lodico@unimi.it.
Abstract:
Glioblastoma (GBM) is the most common astrocytic-derived brain tumor in adults, characterized by a poor prognosis mainly due to the resistance to the available therapy. The study of mitochondria-derived oxidative stress, and of the biological events that orbit around it, might help in the comprehension of the molecular mechanisms at the base of GBM responsiveness to Temozolomide (TMZ). Sensitive and resistant GBM cells were used to test the role of mitochondrial ROS release in TMZ-resistance. Chaperone-Mediated Autophagy (CMA) activation in relation to reactive oxygen species (ROS) release has been measured by monitoring the expression of specific genes. Treatments with H2O2 were used to test their potential in reverting resistance. Fluctuations of cytoplasmic ROS levels were accountable for CMA induction and cytotoxic effects observed in TMZ sensitive cells after treatment. On the other hand, in resistant cells, TMZ failed in producing an increase in cytoplasmic ROS levels and CMA activation, preventing GBM cell toxicity. By increasing oxidative stress, CMA activation was recovered, as also cell cytotoxicity, especially in combination with TMZ treatment. Herein, for the first time, it is shown the relation between mitochondrial ROS release, CMA activation and TMZ-responsiveness in GBM.
Insights
Mitochondrial oxidative stress and Chaperone-Mediated Autophagy (CMA) influence glioblastoma (GBM) resistance to Temozolomide (TMZ). Enhancing oxidative stress with CMA can restore TMZ sensitivity and cytotoxicity in glioblastoma cells.
Area of Science:
- Oncology
- Cell Biology
- Biochemistry
Background:
- Glioblastoma (GBM) is an aggressive brain tumor with poor prognosis due to therapeutic resistance.
- Understanding molecular mechanisms of GBM resistance to Temozolomide (TMZ) is crucial for improving treatment outcomes.
Purpose of the Study:
- To investigate the role of mitochondria-derived oxidative stress and Chaperone-Mediated Autophagy (CMA) in glioblastoma's response to Temozolomide (TMZ).
- To explore potential strategies for overcoming TMZ resistance in glioblastoma cells.
Main Methods:
- Utilized sensitive and resistant glioblastoma cell lines to assess mitochondrial reactive oxygen species (ROS) release.
- Measured Chaperone-Mediated Autophagy (CMA) activation by monitoring gene expression.
- Applied hydrogen peroxide (H2O2) treatments to evaluate resistance reversal.
Main Results:
- Cytoplasmic ROS fluctuations induced CMA and cytotoxicity in TMZ-sensitive GBM cells.
- TMZ-resistant GBM cells showed no significant increase in ROS or CMA activation, thus resisting toxicity.
- Increasing oxidative stress via CMA activation restored sensitivity and cytotoxicity, particularly when combined with TMZ.
Conclusions:
- Established a novel link between mitochondrial ROS release, CMA activation, and TMZ responsiveness in glioblastoma.
- Demonstrated that enhancing oxidative stress can overcome TMZ resistance in glioblastoma by reactivating CMA.
- Suggests that targeting oxidative stress and CMA pathways may offer new therapeutic strategies for glioblastoma treatment.
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