PIK3CB/p110β is a selective survival factor for glioblastoma
Kevin J Pridham1,2, Lamvy Le1,3, Sujuan Guo1
1Virginia Tech Carilion Research Institute, Virginia Tech, Roanoke, Virginia.
Background:
Glioblastoma (GBM) is difficult to treat. Phosphoinositide 3-kinase (PI3K) is an attractive therapeutic target for GBM; however, targeting this pathway to effectively treat GBM is not successful because the roles of PI3K isoforms remain to be defined. The aim of this study is to determine whether PIK3CB/p110β, but not other PI3K isoforms, is a biomarker for GBM recurrence and important for cell survival.
Methods:
Gene expression and clinical relevance of PI3K genes in GBM patients were analyzed using online databases. Expression/activity of PI3K isoforms was determined using immunoblotting. PI3K genes were inhibited using short hairpin RNAs or isoform-selective inhibitors. Cell viability/growth was assessed by the MTS assay and trypan blue exclusion assay. Apoptosis was monitored using the caspase activity assay. Mouse GBM xenograft models were used to gauge drug efficacy.
Results:
PIK3CB/p110β was the only PI3K catalytic isoform that significantly correlated with high incidence rate, risk, and poor survival of recurrent GBM. PIK3CA/p110α, PIK3CB/p110β, and PIK3CD/p110δ were differentially expressed in GBM cell lines and primary tumor cells derived from patient specimens, whereas PIK3CG/p110γ was barely detected. PIK3CB/p110β protein levels presented a stronger association with the activities of PI3K signaling than other PI3K isoforms. Blocking p110β deactivated PI3K signaling, whereas inhibition of other PI3K isoforms had no effect. Specific inhibitors of PIK3CB/p110β, but not other PI3K isoforms, remarkably suppressed viability and growth of GBM cells and xenograft tumors in mice, with minimal cytotoxic effects on astrocytes.
Conclusions:
PIK3CB/p110β is a biomarker for GBM recurrence and selectively important for GBM cell survival.
Insights
Phosphoinositide 3-kinase beta (PIK3CB/p110β) is a biomarker for glioblastoma recurrence and crucial for cancer cell survival. Targeting PIK3CB/p110β selectively inhibits glioblastoma growth, offering a promising therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Glioblastoma (GBM) presents significant therapeutic challenges.
- Phosphoinositide 3-kinase (PI3K) pathway is a potential therapeutic target, but isoform-specific roles in GBM remain unclear.
- Understanding PI3K isoform function is critical for developing effective GBM treatments.
Purpose of the Study:
- To investigate the role of PIK3CB/p110β as a potential biomarker for GBM recurrence.
- To determine the specific contribution of PIK3CB/p110β to GBM cell survival.
- To evaluate PIK3CB/p110β as a selective therapeutic target in GBM.
Main Methods:
- Analysis of PI3K gene expression and clinical data in GBM patients using online databases.
- Assessment of PI3K isoform expression and activity via immunoblotting.
- Inhibition of PI3K isoforms using short hairpin RNAs and selective inhibitors.
- Evaluation of cell viability, growth, and apoptosis using MTS, trypan blue, and caspase activity assays.
- Assessment of therapeutic efficacy in mouse GBM xenograft models.
Main Results:
- PIK3CB/p110β was the sole PI3K isoform significantly correlated with GBM recurrence, incidence, and poor survival.
- PIK3CB/p110β protein levels strongly correlated with PI3K signaling activity in GBM cells.
- Selective inhibition of PIK3CB/p110β effectively suppressed GBM cell viability, growth, and tumor progression in vivo.
- Inhibition of PIK3CB/p110β demonstrated minimal toxicity to normal astrocytes.
Conclusions:
- PIK3CB/p110β serves as a predictive biomarker for GBM recurrence.
- PIK3CB/p110β plays a selective and critical role in GBM cell survival.
- Targeting PIK3CB/p110β represents a promising and selective therapeutic strategy for glioblastoma.
