Noxa and Mcl-1 expression influence the sensitivity to BH3-mimetics that target Bcl-xL in patient-derived glioma stem
Mariana Belén Vera1, Olivia Morris-Hanon2, Germán Ignacio Nogueiras3
1Laboratorio de Investigación aplicada a Neurociencias (LIAN), Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia (FLENI), Ruta 9, Km 52.5, B1625XAF, Buenos Aires, Argentina. mariana.belen.v.p@gmail.com.
Abstract:
The recurrence of Glioblastoma is partly attributed to the highly resistant subpopulation of glioma stem cells. A novel therapeutic approach focuses on restoring apoptotic programs in these cancer stem cells, as they are often deregulated. BH3-mimetics, targeting anti-apoptotic Bcl-2 family members, are emerging as promising compounds to sensitize cancer cells to antineoplastic treatments. Herein, we determined that the most abundantly expressed anti-apoptotic Bcl-2 family members, Bcl-xL and Mcl-1, are the most relevant in regulating patient-derived glioma stem cell survival. We exposed these cells to routinely used chemotherapeutic drugs and BH3-mimetics (ABT-263, WEHI-539, and S63845). We observed that the combination of BH3-mimetics targeting Bcl-xL with chemotherapeutic agents caused a marked increase in cell death and that this sensitivity to Bcl-xL inhibition correlated with Noxa expression levels. Interestingly, whereas co-targeting Bcl-xL and Mcl-1 led to massive cell death in all tested cell lines, down-regulation of Noxa promoted cell survival only in cell lines expressing higher levels of this BH3-only. Therefore, in glioma stem cells, the efficacy of Bcl-xL inhibition is closely associated with Mcl-1 activity and Noxa expression. Hence, a potentially effective strategy would consist of combining Bcl-xL inhibitors with chemotherapeutic agents capable of inducing Noxa, taking advantage of this pro-apoptotic factor.
Insights
Targeting glioma stem cells with BH3-mimetics can restore apoptosis. Combining Bcl-xL inhibitors with chemotherapy, especially agents inducing Noxa, effectively reduces glioblastoma stem cell survival.
Area of Science:
- Oncology
- Cancer Stem Cell Biology
- Molecular Therapeutics
Background:
- Glioblastoma recurrence is linked to resistant glioma stem cells (GSCs).
- Restoring apoptosis in GSCs is a key therapeutic strategy.
- BH3-mimetics show promise in sensitizing cancer cells.
Purpose of the Study:
- Identify key anti-apoptotic proteins in GSC survival.
- Evaluate BH3-mimetics and chemotherapy combinations against GSCs.
- Determine the role of Noxa in GSC response to therapy.
Main Methods:
- Analysis of Bcl-xL and Mcl-1 expression in patient-derived GSCs.
- Treatment of GSCs with chemotherapy and BH3-mimetics (ABT-263, WEHI-539, S63845).
- Assessment of cell death and correlation with Noxa expression.
Main Results:
- Bcl-xL and Mcl-1 are critical for GSC survival.
- Combining Bcl-xL inhibitors with chemotherapy increased GSC death.
- Noxa expression levels correlated with sensitivity to Bcl-xL inhibition.
- Co-targeting Bcl-xL and Mcl-1 induced massive cell death.
Conclusions:
- Glioblastoma stem cell survival is regulated by Bcl-xL and Mcl-1.
- Efficacy of Bcl-xL inhibition depends on Mcl-1 activity and Noxa levels.
- Combining Bcl-xL inhibitors with Noxa-inducing chemotherapy is a potential therapeutic strategy.
