The Oncogene Addiction Switch from NOTCH to PI3K Requires Simultaneous Targeting of NOTCH and PI3K Pathway Inhibition in Glioblastoma

被引：14

作者：

Saito, Norihiko ^{[1
]}

Hirai, Nozomi ^{[1
]}

Aoki, Kazuya ^{[1
]}

Suzuki, Ryo ^{[1
]}

Fujita, Satoshi ^{[1
]}

Nakayama, Haruo ^{[1
]}

Hayashi, Morito ^{[1
]}

Ito, Keisuke ^{[1
]}

Sakurai, Takatoshi ^{[1
]}

Iwabuchi, Satoshi ^{[1
]}

机构：

[1] Toho Univ, Ohashi Med Ctr, Dept Neurosurg, Tokyo 1538515, Japan

来源：

CANCERS | 2019年 / 11卷 / 01期

关键词：

NOTCH; glioma initiating cell; PTEN; PI3K pathway; glioblastoma; C-MYC; CELLS; PTEN; ACTIVATION; EXPRESSION; RESISTANCE; DIFFERENTIATION; GROWTH; GENES; ROLES;

D O I：

10.3390/cancers11010121

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

The NOTCH pathway regulates neural stem cells and glioma initiating cells (GICs). However, blocking NOTCH activity with gamma-secretase inhibitors (GSIs) fails to alter the growth of GICs, as GSIs seem to be active in only a fraction of GICs lines with constitutive NOTCH activity. Here we report loss of PTEN function as a critical event leading to resistance to NOTCH inhibition, which causes the transfer of oncogene addiction from the NOTCH pathway to the PI3K pathway. Drug cytotoxicity testing of eight GICs showed a differential growth response to GSI, and the GICs were thus stratified into two groups: sensitive and resistant. In the sensitive group, GICs with loss of PTEN function appeared less sensitive to GSI treatment. Here we show that NOTCH regulates PTEN expression and the activity of the PI3K pathway in GICs, as treatment with GSI attenuated the NOTCH pathway and increased PTEN expression. NOTCH regulates PTEN expression via Hes-1, as knockdown of Notch or Hes1 increased expression of PTEN. This novel observation suggests that both pathways must be simultaneously inhibited in order to improve therapeutic efficacy in human glioblastomas (GBMs).

引用

页数：12

共 32 条

[1] High Energy Particle Radiation-associated Oncogenic Transformation in Normal Mice: Insight into the Connection between Activation of Oncotargets and Oncogene Addiction [J].

Aravindan, Natarajan ;

Aravindan, Sheeja ;

Manickam, Krishnan ;

Natarajan, Mohan .

SCIENTIFIC REPORTS, 2016, 6

[2] Targeting cancer stem cells through L1CAM suppresses glioma growth [J].

Bao, Shideng ;

Wu, Qiulian ;

Li, Zhizhong ;

Sathornsumetee, Sith ;

Wang, Hui ;

McLendon, Roger E. ;

Hjehneland, Anita B. ;

Rich, Jeremy N. .

CANCER RESEARCH, 2008, 68 (15) :6043-6048

[3] The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity [J].

Barretina, Jordi ;

Caponigro, Giordano ;

Stransky, Nicolas ;

Venkatesan, Kavitha ;

Margolin, Adam A. ;

Kim, Sungjoon ;

Wilson, Christopher J. ;

Lehar, Joseph ;

Kryukov, Gregory V. ;

Sonkin, Dmitriy ;

Reddy, Anupama ;

Liu, Manway ;

Murray, Lauren ;

Berger, Michael F. ;

Monahan, John E. ;

Morais, Paula ;

Meltzer, Jodi ;

Korejwa, Adam ;

Jane-Valbuena, Judit ;

Mapa, Felipa A. ;

Thibault, Joseph ;

Bric-Furlong, Eva ;

Raman, Pichai ;

Shipway, Aaron ;

Engels, Ingo H. ;

Cheng, Jill ;

Yu, Guoying K. ;

Yu, Jianjun ;

Aspesi, Peter, Jr. ;

de Silva, Melanie ;

Jagtap, Kalpana ;

Jones, Michael D. ;

Wang, Li ;

Hatton, Charles ;

Palescandolo, Emanuele ;

Gupta, Supriya ;

Mahan, Scott ;

Sougnez, Carrie ;

Onofrio, Robert C. ;

Liefeld, Ted ;

MacConaill, Laura ;

Winckler, Wendy ;

Reich, Michael ;

Li, Nanxin ;

Mesirov, Jill P. ;

Gabriel, Stacey B. ;

Getz, Gad ;

Ardlie, Kristin ;

Chan, Vivien ;

Myer, Vic E. .

NATURE, 2012, 483 (7391) :603-607

[4]

Bertrand Fred E., 2014, Advances in Biological Regulation, V56, P51, DOI 10.1016/j.jbior.2014.05.002

[5] The transcriptional coactivator TAZ regulates mesenchymal differentiation in malignant glioma [J].

Bhat, Krishna P. L. ;

Salazar, Katrina L. ;

Balasubramaniyan, Veerakumar ;

Wani, Khalida ;

Heathcock, Lindsey ;

Hollingsworth, Faith ;

James, Johanna D. ;

Gumin, Joy ;

Diefes, Kristin L. ;

Kim, Se Hoon ;

Turski, Alice ;

Azodi, Yasaman ;

Yang, Yuhui ;

Doucette, Tiffany ;

Colman, Howard ;

Sulman, Erik P. ;

Lang, Frederick F. ;

Rao, Ganesh ;

Copray, Sjef ;

Vaillant, Brian D. ;

Aldape, Kenneth D. .

GENES & DEVELOPMENT, 2011, 25 (24) :2594-2609

[6] Glioblastoma Subclasses Can Be Defined by Activity among Signal Transduction Pathways and Associated Genomic Alterations [J].

Brennan, Cameron ;

Momota, Hiroyuki ;

Hambardzumyan, Dolores ;

Ozawa, Tatsuya ;

Tandon, Adesh ;

Pedraza, Alicia ;

Holland, Eric .

PLOS ONE, 2009, 4 (11)

[7] Increased protein expression of the PTEN tumor suppressor in the presence of constitutively active Notch-1 [J].

Chappell, WH ;

Green, TD ;

Spengeman, JD ;

McCubrey, JA ;

Akula, SM ;

Bertrand, FE .

CELL CYCLE, 2005, 4 (10) :1389-1395

[8] Comprehensive genomic characterization defines human glioblastoma genes and core pathways [J].

Chin, L. ;

Meyerson, M. ;

Aldape, K. ;

Bigner, D. ;

Mikkelsen, T. ;

VandenBerg, S. ;

Kahn, A. ;

Penny, R. ;

Ferguson, M. L. ;

Gerhard, D. S. ;

Getz, G. ;

Brennan, C. ;

Taylor, B. S. ;

Winckler, W. ;

Park, P. ;

Ladanyi, M. ;

Hoadley, K. A. ;

Verhaak, R. G. W. ;

Hayes, D. N. ;

Spellman, Paul T. ;

Absher, D. ;

Weir, B. A. ;

Ding, L. ;

Wheeler, D. ;

Lawrence, M. S. ;

Cibulskis, K. ;

Mardis, E. ;

Zhang, Jinghui ;

Wilson, R. K. ;

Donehower, L. ;

Wheeler, D. A. ;

Purdom, E. ;

Wallis, J. ;

Laird, P. W. ;

Herman, J. G. ;

Schuebel, K. E. ;

Weisenberger, D. J. ;

Baylin, S. B. ;

Schultz, N. ;

Yao, Jun ;

Wiedemeyer, R. ;

Weinstein, J. ;

Sander, C. ;

Gibbs, R. A. ;

Gray, J. ;

Kucherlapati, R. ;

Lander, E. S. ;

Myers, R. M. ;

Perou, C. M. ;

McLendon, Roger .

NATURE, 2008, 455 (7216) :1061-1068

[9] Synergistic activity of troxacitabine (Troxatyl ™) and gemcitabine in pancreatic cancer [J].

Damaraju, Vijaya L. ;

Bouffard, David Y. ;

Wong, Clarence K. W. ;

Clarke, Marilyn L. ;

Mackey, John R. ;

Leblond, Lorraine ;

Cass, Carol E. ;

Grey, Mike ;

Gourdeau, Henriette .

BMC CANCER, 2007, 7 (1)

[10] Reduced PTEN expression in breast cancer cells confers susceptibility to inhibitors of the PI3 kinase/Akt pathway [J].

deGraffenried, LA ;

Fulcher, L ;

Friedrichs, WE ;

Grünwald, V ;

Ray, RB ;

Hidalgo, M .

ANNALS OF ONCOLOGY, 2004, 15 (10) :1510-1516

← 1 2 3 4 →