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Expression and function of ABCG2 and XIAP in glioblastomas
Ivette F Emery1, Archana Gopalan2, Stephanie Wood2
1Maine Medical Center Research Institute, 81 Research Drive, Scarborough, ME, 04074, USA. emeryi@mmc.org.
Abstract:
Despite multimodal treatment that includes surgery, radiation and chemotherapy, virtually all glioblastomas (GBM) recur, indicating that these interventions are insufficient to eradicate all malignant cells. To identify potential new therapeutic targets in GBMs, we examined the expression and function of proteins that are associated with therapy resistance and cancer cell survival. We measured the expression of eight such proteins in 50 GBM samples by immunohistochemistry and analyzed patient survival. We report that GBM patients with high expression of ABCG2 (also called BCRP) or XIAP at the protein level had worse survival than those with low expression. The adjusted hazard ratio for ABCG2 was 2.35 and for XIAP was 2.65. Since glioma stem cells (GSCs) have been shown to be more resistant than bulk tumor cells to anti-cancer therapies and to express high levels of these proteins, we also sought to determine if ABCG2 and XIAP have functional roles in GSCs. We used small molecule inhibitors to treat patient-derived GBM tumorspheres in vitro and observed that inhibitors of ABCG2, Ko143 and fumitremorgin, significantly reduced self-renewal. These results suggest that ABCG2 and XIAP proteins may be useful indicators of patient survival and that inhibition of ABCG2 may be a promising therapeutic strategy in GBMs.
Insights
Glioblastoma (GBM) often recurs after treatment. High levels of ABCG2 and XIAP proteins correlate with worse survival, suggesting they are key targets for new glioblastoma therapies.
Area of Science:
- Neuro-oncology
- Cancer Biology
- Molecular Medicine
Background:
- Glioblastoma (GBM) frequently recurs despite multimodal treatments.
- Therapy resistance and cancer cell survival mechanisms in GBM remain incompletely understood.
- Glioma stem cells (GSCs) exhibit enhanced resistance to therapies.
Purpose of the Study:
- To identify novel therapeutic targets in GBM by examining proteins linked to therapy resistance.
- To investigate the expression and functional role of ABCG2 and XIAP in GBM and GSCs.
- To evaluate the potential of targeting ABCG2 as a therapeutic strategy.
Main Methods:
- Immunohistochemistry was used to measure the expression of eight proteins in 50 GBM samples.
- Patient survival data was analyzed in correlation with protein expression levels.
- Patient-derived GBM tumorspheres were treated in vitro with small molecule inhibitors of ABCG2.
Main Results:
- High protein expression of ABCG2 (BCRP) and XIAP was associated with significantly worse patient survival (HR=2.35 for ABCG2, HR=2.65 for XIAP).
- GSCs express high levels of ABCG2 and XIAP.
- Inhibitors targeting ABCG2 (Ko143, fumitremorgin) significantly reduced GSC self-renewal in vitro.
Conclusions:
- ABCG2 and XIAP are potential prognostic indicators for GBM patient survival.
- Targeting ABCG2 presents a promising therapeutic strategy for overcoming GBM therapy resistance.
- Further research into ABCG2 and XIAP functions may reveal new avenues for GBM treatment.
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