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Published on: October 11, 2017
Targeting the miR-19b/PPP2R5E axis enhances temozolomide response in glioblastoma via ROS-induced DNA damage
Elham Kashani1, Martin C Sadowski2, Jaison Phour2
1Institute of Tissue Medicine and Pathology, University of Bern, Bern, Switzerland. elham.kashani@unibe.ch.
Background:
Glioblastoma is the most aggressive primary brain tumor. Although temozolomide induces DNA damage, its efficacy is limited by intrinsic resistance mechanisms, leading to tumor relapse. In this study we aimed to identify microRNA-mediated resistance mechanisms.
Methods:
MicroRNA screens were performed to identify temozolomide resistance mechanisms. Temozolomide response was evaluated using clonogenic and spheroid assays in glioblastoma cell lines and patient-derived primary cells. DNA damage response was assessed by γH2AX foci formation. Cell cycle distribution, senescence and ferroptosis were assessed following miR-19b attenuation. An orthotopic xenograft and a syngeneic mouse model were used to confirm findings.
Results:
Our screen and subsequent phosphoprotein analysis identified miR-19b and its target PPP2R5E, a subunit of the phosphatase PP2A, as modulators of temozolomide response. Attenuation of miR-19b upregulated PPP2R5E, inducing genotoxic stress, thereby enhancing temozolomide response. Mechanistically, DNA damage correlated with elevated nuclear ROS, promoting senescence and ferroptosis. Consistently, pharmacological activation of PP2A with FTY720 phenocopied the effects of miR-19b suppression. Conversely, knockdown of PPP2R5E reversed temozolomide sensitisation in vitro, in vivo, and ex vivo models, confirming the critical role of the miR-19b/PPP2R5E axis in modulating drug response.
Conclusions:
Therapeutic targeting of the PPP2R5E/PP2A complexes holds promise for enhanced temozolomide efficacy in glioblastoma.
Insights
This study identifies miR-19b as a key factor in glioblastoma resistance to temozolomide. Suppressing miR-19b enhances drug efficacy by upregulating PPP2R5E, offering a new therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Glioblastoma is an aggressive brain tumor with limited treatment options.
- Temozolomide efficacy is hampered by intrinsic resistance mechanisms, leading to tumor recurrence.
- MicroRNA-mediated resistance pathways remain incompletely understood.
Purpose of the Study:
- To identify microRNA-mediated resistance mechanisms against temozolomide in glioblastoma.
- To elucidate the role of specific microRNAs and their targets in modulating drug response.
- To explore novel therapeutic strategies for overcoming temozolomide resistance.
Main Methods:
- Conducted microRNA screens to identify resistance mechanisms.
- Evaluated temozolomide response using clonogenic and spheroid assays in glioblastoma cells and patient-derived cells.
- Assessed DNA damage, cell cycle, senescence, and ferroptosis following miR-19b modulation.
- Utilized orthotopic xenograft and syngeneic mouse models for in vivo validation.
Main Results:
- Identified miR-19b and its target PPP2R5E as key modulators of temozolomide response.
- miR-19b suppression upregulated PPP2R5E, enhancing temozolomide efficacy through genotoxic stress, senescence, and ferroptosis.
- Pharmacological activation of PP2A mimicked miR-19b suppression effects.
- Knockdown of PPP2R5E reversed temozolomide sensitization in vitro and in vivo.
Conclusions:
- The miR-19b/PPP2R5E axis plays a critical role in glioblastoma's response to temozolomide.
- Targeting PPP2R5E/PP2A complexes offers a promising strategy to enhance temozolomide efficacy.
- This research opens avenues for novel combination therapies in glioblastoma treatment.
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