Dual inhibition of Src and PLK1 regulate stemness and induce apoptosis through Notch1-SOX2 signaling in EGFRvIII positive glioma stem cells (GSCs)

Exp Cell Res. 2020 Nov 1;396(1):112261. doi: 10.1016/j.yexcr.2020.112261. Epub 2020 Sep 5.

Abstract

Glioma stem cells (GSCs) have been implicated in the promotion of malignant progression. Epidermal growth factor receptor variant (EGFRv) has been associated with glioma "stemness". However, the molecular mechanism is not clear. In this study, we were committed to investigate the role of EGFRv in GSCs and presented a new therapeutic target in EGFRvIII positive GSCs. The results showed that EGFRvIII could induce the expression of p-Src and PLK1, and both could induce the Notch1-SOX2 signaling pathway to promote self-renewal and tumor progression of GSCs. Mechanistically, both p-Src and PLK1 can induce Notch1, and the intracellular domain of Notch1 (NICD) can directly bind to SOX2, thereby promoting the maintenance of glioma stem cells. Furthermore, Saracatinib (Src inhibition) and BI2536 (PLK1 inhibition) diminished GSC self-renewal in vitro, and combining the two inhibitors increased survival of orthotopic tumor-bearing mice. Taken together, these data indicate that p-Src and PLK1 contribute to cancer stemness in EGFRvIII-positive GSCs by driving Notch1-SOX2 signaling, a finding that has important clinical implications.

Keywords: EGFRvIII; Glioma stem cells (GSCs); Notch1-SOX2; PLK1; p-Src.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Benzodioxoles / pharmacology
  • Brain Neoplasms / drug therapy*
  • Brain Neoplasms / genetics
  • Brain Neoplasms / metabolism
  • Brain Neoplasms / mortality
  • Cell Cycle Proteins / antagonists & inhibitors
  • Cell Cycle Proteins / genetics*
  • Cell Cycle Proteins / metabolism
  • Cell Line, Tumor
  • ErbB Receptors / genetics
  • ErbB Receptors / metabolism
  • Female
  • Gene Expression Regulation, Neoplastic
  • Glioma / drug therapy*
  • Glioma / genetics
  • Glioma / metabolism
  • Glioma / mortality
  • Humans
  • Injections, Intraventricular
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Neoplastic Stem Cells / drug effects
  • Neoplastic Stem Cells / metabolism
  • Neoplastic Stem Cells / pathology
  • Polo-Like Kinase 1
  • Protein Serine-Threonine Kinases / antagonists & inhibitors
  • Protein Serine-Threonine Kinases / genetics*
  • Protein Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins / antagonists & inhibitors
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins / metabolism
  • Pteridines / pharmacology
  • Quinazolines / pharmacology
  • Receptor, Notch1 / genetics*
  • Receptor, Notch1 / metabolism
  • SOXB1 Transcription Factors / genetics*
  • SOXB1 Transcription Factors / metabolism
  • Signal Transduction
  • Stereotaxic Techniques
  • Survival Analysis
  • Tumor Burden / drug effects
  • Xenograft Model Antitumor Assays
  • src-Family Kinases / antagonists & inhibitors
  • src-Family Kinases / genetics*
  • src-Family Kinases / metabolism

Substances

  • Antineoplastic Agents
  • BI 2536
  • Benzodioxoles
  • Cell Cycle Proteins
  • NOTCH1 protein, human
  • Proto-Oncogene Proteins
  • Pteridines
  • Quinazolines
  • Receptor, Notch1
  • SOX2 protein, human
  • SOXB1 Transcription Factors
  • epidermal growth factor receptor VIII
  • saracatinib
  • ErbB Receptors
  • src-Family Kinases
  • Protein Serine-Threonine Kinases