PIK3CB/p110β is a selective survival factor for glioblastoma

Kevin J. Pridham, Lamvy Le, Sujuan Guo, Robin T. Varghese, Sarah Algino, Yanping Liang, Renee Fajardin, Cara M. Rodgers, Gary R. Simonds, Deborah F. Kelly, Zhi Sheng

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

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/p110Î were differentially expressed in GBM cell lines and primary tumor cells derived from patient specimens, whereas PIK3CG/p110Î 3 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.

Original languageEnglish (US)
Pages (from-to)494-505
Number of pages12
JournalNeuro-oncology
Volume20
Issue number4
DOIs
StatePublished - Mar 27 2018

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1-Phosphatidylinositol 4-Kinase
Glioblastoma
Survival
Protein Isoforms
Cell Survival
Tumor Cell Line
Heterografts
Biomarkers
RNA Isoforms
Recurrence
Trypan Blue
Growth
Caspases
Immunoblotting
Astrocytes
Small Interfering RNA
Genes

All Science Journal Classification (ASJC) codes

  • Oncology
  • Clinical Neurology
  • Cancer Research

Cite this

Pridham, K. J., Le, L., Guo, S., Varghese, R. T., Algino, S., Liang, Y., ... Sheng, Z. (2018). PIK3CB/p110β is a selective survival factor for glioblastoma. Neuro-oncology, 20(4), 494-505. https://doi.org/10.1093/neuonc/nox181
Pridham, Kevin J. ; Le, Lamvy ; Guo, Sujuan ; Varghese, Robin T. ; Algino, Sarah ; Liang, Yanping ; Fajardin, Renee ; Rodgers, Cara M. ; Simonds, Gary R. ; Kelly, Deborah F. ; Sheng, Zhi. / PIK3CB/p110β is a selective survival factor for glioblastoma. In: Neuro-oncology. 2018 ; Vol. 20, No. 4. pp. 494-505.
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title = "PIK3CB/p110β is a selective survival factor for glioblastoma",
abstract = "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/p110{\^I} were differentially expressed in GBM cell lines and primary tumor cells derived from patient specimens, whereas PIK3CG/p110{\^I} 3 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.",
author = "Pridham, {Kevin J.} and Lamvy Le and Sujuan Guo and Varghese, {Robin T.} and Sarah Algino and Yanping Liang and Renee Fajardin and Rodgers, {Cara M.} and Simonds, {Gary R.} and Kelly, {Deborah F.} and Zhi Sheng",
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Pridham, KJ, Le, L, Guo, S, Varghese, RT, Algino, S, Liang, Y, Fajardin, R, Rodgers, CM, Simonds, GR, Kelly, DF & Sheng, Z 2018, 'PIK3CB/p110β is a selective survival factor for glioblastoma', Neuro-oncology, vol. 20, no. 4, pp. 494-505. https://doi.org/10.1093/neuonc/nox181

PIK3CB/p110β is a selective survival factor for glioblastoma. / Pridham, Kevin J.; Le, Lamvy; Guo, Sujuan; Varghese, Robin T.; Algino, Sarah; Liang, Yanping; Fajardin, Renee; Rodgers, Cara M.; Simonds, Gary R.; Kelly, Deborah F.; Sheng, Zhi.

In: Neuro-oncology, Vol. 20, No. 4, 27.03.2018, p. 494-505.

Research output: Contribution to journalArticle

TY - JOUR

T1 - PIK3CB/p110β is a selective survival factor for glioblastoma

AU - Pridham, Kevin J.

AU - Le, Lamvy

AU - Guo, Sujuan

AU - Varghese, Robin T.

AU - Algino, Sarah

AU - Liang, Yanping

AU - Fajardin, Renee

AU - Rodgers, Cara M.

AU - Simonds, Gary R.

AU - Kelly, Deborah F.

AU - Sheng, Zhi

PY - 2018/3/27

Y1 - 2018/3/27

N2 - 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/p110Î were differentially expressed in GBM cell lines and primary tumor cells derived from patient specimens, whereas PIK3CG/p110Î 3 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.

AB - 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/p110Î were differentially expressed in GBM cell lines and primary tumor cells derived from patient specimens, whereas PIK3CG/p110Î 3 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.

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Pridham KJ, Le L, Guo S, Varghese RT, Algino S, Liang Y et al. PIK3CB/p110β is a selective survival factor for glioblastoma. Neuro-oncology. 2018 Mar 27;20(4):494-505. https://doi.org/10.1093/neuonc/nox181