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

被引：122

作者：

Garros-Regulez, Laura ^{[1
]}

Aldaz, Paula ^{[1
]}

Arrizabalaga, Olatz ^{[1
]}

Moncho-Amor, Veronica ^{[3
]}

Carrasco-Garcia, Estefania ^{[1
]}

Manterola, Lorea ^{[1
]}

Moreno-Cugnon, Leire ^{[1
]}

Barrena, Cristina ^{[2
]}

Villanua, Jorge ^{[1
,2
]}

Ruiz, Irune ^{[1
,2
]}

Pollard, Steven ^{[4
]}

Lovell-Badge, Robin ^{[3
]}

Sampron, Nicolas ^{[1
,2
]}

Garcia, Idoia ^{[1
,5
]}

Matheu, Ander ^{[1
,2
,5
]}

机构：

[1] Biodonostia Inst, Cellular Oncol Grp, Paseo Dr Beguiristain S-N, E-20014 San Sebastian, Spain

[2] Donostia Hosp, Neurooncol Comm, San Sebastian, Spain

[3] Francis Crick Inst, Stem Cell Biol & Dev Genet Lab, London, England

[4] MRC Ctr Regenerat Med, Neural Stem Cells & Brain Canc Grp, Edinburgh, Midlothian, Scotland

[5] Basque Fdn Sci, Ikerbasque, Bilbao, Spain

来源：

EXPERT OPINION ON THERAPEUTIC TARGETS | 2016年 / 20卷 / 04期

关键词：

SOX9; SOX2; Glioma stem cell; rapamycin and temozolomide; senescence; TUMOR-INITIATING CELLS; TRANSCRIPTION FACTORS; ADJUVANT TEMOZOLOMIDE; PROGENITOR CELLS; SOX2; EXPRESSION; GLIOBLASTOMA; CANCER; PATHWAY; TUMORIGENICITY; IDENTIFICATION;

D O I：

10.1517/14728222.2016.1151002

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

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.

引用

页码：393 / 405

页数：13

共 47 条

[1]

de la Rocha AMA, 2014, AM J CANCER RES, V4, P312

[2] A complex secretory program orchestrated by the inflammasome controls paracrine senescence [J].

Acosta, Juan Carlos ;

Banito, Ana ;

Wuestefeld, Torsten ;

Georgilis, Athena ;

Janich, Peggy ;

Morton, Jennifer P. ;

Athineos, Dimitris ;

Kang, Tae-Won ;

Lasitschka, Felix ;

Andrulis, Mindaugas ;

Pascual, Gloria ;

Morris, Kelly J. ;

Khan, Sadaf ;

Jin, Hong ;

Dharmalingam, Gopuraja ;

Snijders, Ambrosius P. ;

Carroll, Thomas ;

Capper, David ;

Pritchard, Catrin ;

Inman, Gareth J. ;

Longerich, Thomas ;

Sansom, Owen J. ;

Aznar Benitah, Salvador ;

Zender, Lars ;

Gil, Jesus .

NATURE CELL BIOLOGY, 2013, 15 (08) :978-U221

[3] Genetic and Epigenetic Modifications of Sox2 Contribute to the Invasive Phenotype of Malignant Gliomas [J].

Alonso, Marta M. ;

Diez-Valle, Ricardo ;

Manterola, Lorea ;

Rubio, Angel ;

Liu, Dan ;

Cortes-Santiago, Nahir ;

Urquiza, Leire ;

Jauregi, Patricia ;

Lopez de Munain, Adolfo ;

Sampron, Nicolas ;

Aramburu, Ander ;

Tejada-Solis, Sonia ;

Vicente, Carmen ;

Odero, Maria D. ;

Bandres, Eva ;

Garcia-Foncillas, Jesus ;

Idoate, Miguel A. ;

Lang, Frederick F. ;

Fueyo, Juan ;

Gomez-Manzano, Candelaria .

PLOS ONE, 2011, 6 (11)

[4]

Annovazzi L, 2011, CANCER GENOM PROTEOM, V8, P139

[5] Multipotent cell lineages in early mouse development depend on SOX2 function [J].

Avilion, AA ;

Nicolis, SK ;

Pevny, LH ;

Perez, L ;

Vivian, N ;

Lovell-Badge, R .

GENES & DEVELOPMENT, 2003, 17 (01) :126-140

[6] Glioma stem cells promote radioresistance by preferential activation of the DNA damage response [J].

Bao, Shideng ;

Wu, Qiulian ;

McLendon, Roger E. ;

Hao, Yueling ;

Shi, Qing ;

Hjelmeland, Anita B. ;

Dewhirst, Mark W. ;

Bigner, Darell D. ;

Rich, Jeremy N. .

NATURE, 2006, 444 (7120) :756-760

[7] An embryonic stem cell-like gene expression signature in poorly differentiated aggressive human tumors [J].

Ben-Porath, Ittai ;

Thomson, Matthew W. ;

Carey, Vincent J. ;

Ge, Ruping ;

Bell, George W. ;

Regev, Aviv ;

Weinberg, Robert A. .

NATURE GENETICS, 2008, 40 (05) :499-507

[8] Sequentially acting Sox transcription factors in neural lineage development [J].

Bergsland, Maria ;

Ramskold, Daniel ;

Zaouter, Cecile ;

Klum, Susanne ;

Sandberg, Rickard ;

Muhr, Jonas .

GENES & DEVELOPMENT, 2011, 25 (23) :2453-2464

[9] The Somatic Genomic Landscape of Glioblastoma [J].

Brennan, Cameron W. ;

Verhaak, Roel G. W. ;

McKenna, Aaron ;

Campos, Benito ;

Noushmehr, Houtan ;

Salama, Sofie R. ;

Zheng, Siyuan ;

Chakravarty, Debyani ;

Sanborn, J. Zachary ;

Berman, Samuel H. ;

Beroukhim, Rameen ;

Bernard, Brady ;

Wu, Chang-Jiun ;

Genovese, Giannicola ;

Shmulevich, Ilya ;

Barnholtz-Sloan, Jill ;

Zou, Lihua ;

Vegesna, Rahulsimham ;

Shukla, Sachet A. ;

Ciriello, Giovanni ;

Yung, W. K. ;

Zhang, Wei ;

Sougnez, Carrie ;

Mikkelsen, Tom ;

Aldape, Kenneth ;

Bigner, Darell D. ;

Van Meir, Erwin G. ;

Prados, Michael ;

Sloan, Andrew ;

Black, Keith L. ;

Eschbacher, Jennifer ;

Finocchiaro, Gaetano ;

Friedman, William ;

Andrews, David W. ;

Guha, Abhijit ;

Iacocca, Mary ;

O'Neill, Brian P. ;

Foltz, Greg ;

Myers, Jerome ;

Weisenberger, Daniel J. ;

Penny, Robert ;

Kucherlapati, Raju ;

Perou, Charles M. ;

Hayes, D. Neil ;

Gibbs, Richard ;

Marra, Marco ;

Mills, Gordon B. ;

Lander, Eric ;

Spellman, Paul ;

Wilson, Richard .

CELL, 2013, 155 (02) :462-477

[10] Increased gene dosage of Ink4/Arf and p53 delays age-associated central nervous system functional decline [J].

Carrasco-Garcia, Estefania ;

Arrizabalaga, Olatz ;

Serrano, Manuel ;

Lovell-Badge, Robin ;

Matheu, Ander .

AGING CELL, 2015, 14 (04) :710-714

← 1 2 3 4 5 →