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Glioma-derived cancer stem cells are hypersensitive to proteasomal inhibition
Young Dong Yoo1,2, Dae-Hee Lee3,4, Hyunjoo Cha-Molstad5
1Protein Metabolism Medical Research Center and Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul, Korea.
Abstract:
Although proteasome inhibitors (PIs) are used as anticancer drugs to treat various cancers, their relative therapeutic efficacy on stem cells vs. bulk cancers remains unknown. Here, we show that stem cells derived from gliomas, GSCs, are up to 1,000-fold more sensitive to PIs (IC50, 27-70 nM) compared with their differentiated controls (IC50, 47 to »100 μM). The stemness of GSCs correlates to increased ubiquitination, whose misregulation readily triggers apoptosis. PI-induced apoptosis of GSCs is independent of NF-κB but involves the phosphorylation of c-Jun N-terminal kinase as well as the transcriptional activation of endoplasmic reticulum (ER) stress-associated proapoptotic mediators. In contrast to the general notion that ER stress-associated apoptosis is signaled by prolonged unfolded protein response (UPR), GSC-selective apoptosis is instead counteracted by the UPR ATF3 is a key mediator in GSC-selective apoptosis. Pharmaceutical uncoupling of the UPR from its downstream apoptosis sensitizes GSCs to PIs in vitro and during tumorigenesis in mice. Thus, a combinational treatment of a PI with an inhibitor of UPR-coupled apoptosis may enhance targeting of stem cells in gliomas.
Insights
Glioma stem cells (GSCs) are highly sensitive to proteasome inhibitors (PIs), unlike bulk cancer cells. Targeting the unfolded protein response (UPR) alongside PIs may improve glioma stem cell eradication.
Area of Science:
- Oncology
- Cancer Stem Cell Biology
- Molecular Therapeutics
Background:
- Proteasome inhibitors (PIs) are utilized in cancer therapy, but their differential impact on cancer stem cells versus bulk tumor cells is not well understood.
- Glioma stem cells (GSCs) possess unique biological characteristics that may influence their response to therapeutic agents.
Purpose of the Study:
- To investigate the differential sensitivity of GSCs and their differentiated counterparts to proteasome inhibitors.
- To elucidate the molecular mechanisms underlying GSC sensitivity to PIs, focusing on ubiquitination, apoptosis, and endoplasmic reticulum (ER) stress pathways.
- To explore novel therapeutic strategies combining PIs with modulators of ER stress and unfolded protein response (UPR) for enhanced GSC targeting.
Main Methods:
- Comparative analysis of PI sensitivity (IC50 values) between patient-derived GSCs and their differentiated cells.
- Assessment of ubiquitination levels, apoptosis induction, and signaling pathways (NF-κB, c-Jun N-terminal kinase) in response to PI treatment.
- Investigation of the role of ER stress and UPR in PI-induced GSC apoptosis using molecular and pharmacological approaches.
- In vitro and in vivo (murine model) evaluation of combination therapies involving PIs and UPR inhibitors.
Main Results:
- GSCs exhibited significantly higher sensitivity to PIs (up to 1,000-fold) compared to differentiated glioma cells.
- PI-induced apoptosis in GSCs was linked to increased ubiquitination, c-Jun N-terminal kinase phosphorylation, and ER stress-associated mediators, independent of NF-κB.
- The UPR, contrary to general expectations, counteracted GSC-selective apoptosis, with ATF3 identified as a key mediator.
- Pharmacological uncoupling of the UPR from downstream apoptosis sensitized GSCs to PIs, reducing tumor growth in mice.
Conclusions:
- GSCs are uniquely vulnerable to proteasome inhibitors due to their specific ubiquitination and apoptotic signaling pathways.
- The unfolded protein response plays a complex, counterapoptotic role in GSCs treated with PIs.
- Combination therapy targeting both proteasome activity and UPR-coupled apoptosis presents a promising strategy for eradicating glioma stem cells and improving therapeutic outcomes.
