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Published on: October 27, 2014
BIRC3 is a novel driver of therapeutic resistance in Glioblastoma
Dapeng Wang1,2, Anders Berglund3, Rajappa S Kenchappa1,2
1Department of Neuro-Oncology, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612 USA.
Abstract:
Genome-wide analysis of glioblastoma (GBM) reveals pervasive aberrations in apoptotic signaling pathways that collectively contribute to therapeutic resistance. Inhibitors of apoptosis proteins (IAP) exert critical control on the terminal segment of apoptosis leading to apoptosis evasion. In this study, we uncover a unique role for BIRC3, as an IAP that is critical in GBM in response to therapy. Using the TCGA dataset of 524 unique samples, we identify BIRC3 is the only IAP whose differential expression is associated with long-term survival in GBM patients. Using patient tissue samples we further show that BIRC3 expression increases with recurrence. When extrapolated to a preclinical model of a human GBM cell line, we find an increase in BIRC3 expression in response to irradiation (RT) and temozolomide (TMZ) treatment. More importantly, we mechanistically implicate STAT3 and PI3K signaling pathways as drivers of RT-induced up-regulation of BIRC3 expression. Lastly, we demonstrate that both in-vivo and in-vitro BIRC3 up-regulation results in apoptosis evasion and therapeutic resistance in GBM. Collectively, our study identifies a novel translational and targetable role for BIRC3 expression as a predictor of aggressiveness and therapeutic resistance to TMZ and RT mediated by STAT3 and PI3K signaling in GBM.
Insights
BIRC3, an inhibitor of apoptosis protein (IAP), is upregulated in glioblastoma (GBM) and predicts poor survival. Targeting BIRC3 may overcome resistance to radiation (RT) and temozolomide (TMZ) therapy in GBM.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Glioblastoma (GBM) exhibits widespread apoptosis pathway dysregulation, contributing to treatment resistance.
- Inhibitors of Apoptosis Proteins (IAPs) are key regulators of the final steps of apoptosis, enabling cancer cells to evade programmed cell death.
Purpose of the Study:
- To investigate the role of BIRC3, an IAP, in glioblastoma (GBM) response to therapy.
- To identify BIRC3 as a potential biomarker for GBM aggressiveness and therapeutic resistance.
Main Methods:
- Genome-wide analysis of TCGA glioblastoma (GBM) dataset (524 samples).
- Analysis of patient tissue samples for BIRC3 expression in recurrent GBM.
- Preclinical studies using GBM cell lines treated with irradiation (RT) and temozolomide (TMZ).
- Mechanistic investigation implicating STAT3 and PI3K signaling pathways.
Main Results:
- BIRC3 is the only IAP differentially expressed and associated with long-term survival in GBM patients.
- BIRC3 expression increases with GBM recurrence and in response to RT and TMZ treatment.
- STAT3 and PI3K signaling pathways drive RT-induced BIRC3 upregulation.
- Upregulated BIRC3 promotes apoptosis evasion and therapeutic resistance in GBM models.
Conclusions:
- BIRC3 plays a critical role in GBM therapy resistance by promoting apoptosis evasion.
- BIRC3 expression serves as a predictive biomarker for GBM aggressiveness and resistance to TMZ and RT.
- Targeting BIRC3, potentially via modulation of STAT3 and PI3K pathways, offers a novel therapeutic strategy for GBM.
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