Journal
EXPERT OPINION ON THERAPEUTIC TARGETS
Volume 20, Issue 4, Pages 393-405Publisher
TAYLOR & FRANCIS LTD
DOI: 10.1517/14728222.2016.1151002
Keywords
SOX9; SOX2; Glioma stem cell; rapamycin and temozolomide; senescence
Categories
Funding
- Industry Department of Basque Government [SAIO13-PC11BN002, 12-PE12BNO13, SAIO13-PC13BN011]
- Association for International Cancer Research (AICR) [13-1270]
- FEDER [CP10/00539, PI13/02277]
- European Union under Marie Curie Career Integration Grant [2012/712404]
- Pyrenees Biomedical Network [13/BIOD/009, 13/BIOD/011]
- Department of Education, University and Research of Basque Government
- Spanish Association Against Cancer (AECC Gipuzkoa)
- Spanish Ministry of Economy and Competition
- Medical Research Council [MC_U117562207] Funding Source: researchfish
- The Francis Crick Institute [10108, 10109, 10107] Funding Source: researchfish
- Worldwide Cancer Research [13-1270] Funding Source: researchfish
- MRC [MC_U117562207] Funding Source: UKRI
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Background: SOX2 and SOX9 are commonly overexpressed in glioblastoma, and regulate the activity of glioma stem cells (GSCs). Their specific and overlapping roles in GSCs and glioma treatment remain unclear. Methods: SOX2 and SOX9 levels were examined in human biopsies. Gain and loss of function determined the impact of altering SOX2 and SOX9 on cell proliferation, senescence, stem cell activity, tumorigenesis and chemoresistance. Results: SOX2 and SOX9 expression correlates positively in glioma cells and glioblastoma biopsies. High levels of SOX2 bypass cellular senescence and promote resistance to temozolomide. Mechanistic investigations revealed that SOX2 acts upstream of SOX9. mTOR genetic and pharmacologic (rapamycin) inhibition decreased SOX2 and SOX9 expression, and reversed chemoresistance. Conclusions: Our findings reveal SOX2-SOX9 as an oncogenic axis that regulates stem cell properties and chemoresistance. We identify that rapamycin abrogate SOX protein expression and provide evidence that a combination of rapamycin and temozolomide inhibits tumor growth in cells with high SOX2/SOX9.
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