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mTOR inhibition decreases SOX2-SOX9 mediated glioma stem cell activity and temozolomide resistance

Laura Garros-Regulez1, Paula Aldaz1, Olatz Arrizabalaga1

  • 1a Cellular Oncology group , Biodonostia Institute , San Sebastian , Spain.

Expert Opinion on Therapeutic Targets
|February 16, 2016
PubMed
Abstract

Insights

SOX2 and SOX9 proteins drive glioblastoma stem cell growth and chemoresistance. Inhibiting mTOR with rapamycin reduces these proteins, enhancing temozolomide treatment effectiveness.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Stem Cell Research

Background:

  • SOX2 and SOX9 are frequently overexpressed in glioblastoma (GBM).
  • These transcription factors regulate glioma stem cells (GSCs), but their precise roles in GBM and treatment response are not fully understood.

Purpose of the Study:

  • To elucidate the specific and overlapping functions of SOX2 and SOX9 in GSCs.
  • To investigate their impact on glioblastoma progression and resistance to therapy.

Main Methods:

  • Analysis of SOX2 and SOX9 expression in human glioblastoma biopsies.
  • In vitro and in vivo gain- and loss-of-function studies to assess effects on cell proliferation, senescence, stemness, tumorigenesis, and chemoresistance.
  • Investigating the mechanistic link between SOX2, SOX9, and the mTOR pathway.

Main Results:

  • SOX2 and SOX9 expression levels are positively correlated in glioma cells and patient samples.
  • Elevated SOX2 promotes resistance to temozolomide by bypassing cellular senescence.
  • SOX2 functions upstream of SOX9, and mTOR inhibition (genetic or with rapamycin) downregulates both SOX2 and SOX9, reversing chemoresistance.

Conclusions:

  • The SOX2-SOX9 axis is identified as a critical regulator of stem cell properties and chemoresistance in glioblastoma.
  • Rapamycin effectively abrogates SOX protein expression.
  • Combination therapy of rapamycin and temozolomide demonstrates efficacy in inhibiting tumor growth in glioblastomas with high SOX2/SOX9 expression.
Keywords:
Glioma stem cellSOX2SOX9rapamycin and temozolomidesenescence

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