Tight regulation between cell survival and programmed cell death in GBM stem-like cells by EGFR/GSK3b/PP2A signaling

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• 作者：Demirkan B. Gürsel ; Matei A. Banu ; Nicholas Berry…
• 关键词：Glioblastoma ; Cancer stem cells ; EGFR ; Glycogen synthase kinase 3 ; PP2A ; Apoptosis
• 刊名：Journal of Neuro-Oncology
• 出版年：2015
• 出版时间：January 2015
• 年：2015
• 卷：121
• 期：1
• 页码：19-29
• 全文大小：4,599 KB
• 参考文献：1. Bleau AM, Howard BM, Taylor LA, Gursel D, Greenfield JP, Lim Tung HY, Holland EC, Boockvar JA (2008) New strategy for the analysis of phenotypic marker antigens in brain tumor-derived neurospheres in mice and humans. Neurosurg Focus 24:E28. doi:10.3171/FOC/2008/24/3-4/E27 CrossRef
  2. Pollard SM, Yoshikawa K, Clarke ID, Danovi D, Stricker S, Russell R, Bayani J, Head R, Lee M, Bernstein M, Squire JA, Smith A, Dirks P (2009) Glioma stem cell lines expanded in adherent culture have tumor-specific phenotypes and are suitable for chemical and genetic screens. Cell Stem Cell 4:568-80. doi:10.1016/j.stem.2009.03.014 CrossRef
  3. Sanai N, Alvarez-Buylla A, Berger MS (2005) Neural stem cells and the origin of gliomas. N Engl J Med 353:811-22. doi:10.1056/NEJMra043666 CrossRef
  4. Wang JC (2007) Evaluating therapeutic efficacy against cancer stem cells: new challenges posed by a new paradigm. Cell Stem Cell 1:497-01 CrossRef
  5. Gursel DB, Shin BJ, Burkhardt JK, Kesavabhotla K, Schlaff CD, Boockvar JA (2011) Glioblastoma stem-like cells-biology and therapeutic implications. Cancers 3:2655-666. doi:10.3390/cancers3022655 CrossRef
  6. Embi N, Rylatt DB, Cohen P (1980) Glycogen synthase kinase-3 from rabbit skeletal muscle. Separation from cyclic-AMP-dependent protein kinase and phosphorylase kinase. Eur J biochem/FEBS 107:519-27 CrossRef
  7. Ring DB, Johnson KW, Henriksen EJ, Nuss JM, Goff D, Kinnick TR, Ma ST, Reeder JW, Samuels I, Slabiak T, Wagman AS, Hammond ME, Harrison SD (2003) Selective glycogen synthase kinase 3 inhibitors potentiate insulin activation of glucose transport and utilization in vitro and in vivo. Diabetes 52:588-95 CrossRef
  8. Ougolkov AV, Fernandez-Zapico ME, Bilim VN, Smyrk TC, Chari ST, Billadeau DD (2006) Aberrant nuclear accumulation of glycogen synthase kinase-3beta in human pancreatic cancer: association with kinase activity and tumor dedifferentiation. Clinical cancer research : an official journal of the American Association for Cancer Research 12:5074-081. doi:10.1158/1078-0432.CCR-06-0196 CrossRef
  9. Ougolkov AV, Billadeau DD (2006) Targeting GSK-3: a promising approach for cancer therapy? Future Oncol 2:91-00. doi:10.2217/14796694.2.1.91 CrossRef
  10. Kang T, Wei Y, Honaker Y, Yamaguchi H, Appella E, Hung MC, Piwnica-Worms H (2008) GSK-3 beta targets Cdc25A for ubiquitin-mediated proteolysis, and GSK-3 beta inactivation correlates with Cdc25A overproduction in human cancers. Cancer Cell 13:36-7. doi:10.1016/j.ccr.2007.12.002 CrossRef
  11. Ding Q, Xia W, Liu JC, Yang JY, Lee DF, Xia J, Bartholomeusz G, Li Y, Pan Y, Li Z, Bargou RC, Qin J, Lai CC, Tsai FJ, Tsai CH, Hung MC (2005) Erk associates with and primes GSK-3beta for its inactivation resulting in upregulation of beta-catenin. Mol Cell 19:159-70. doi:10.1016/j.molcel.2005.06.009 CrossRef
  12. Shi CS, Huang NN, Harrison K, Han SB, Kehrl JH (2006) The mitogen-activated protein kinase kinase kinase kinase GCKR positively regulates canonical and noncanonical Wnt signaling in B lymphocytes. Mol Cell Biol 26:6511-521. doi:10.1128/MCB.00209-06 CrossRef
  13. Lenferink AE, Busse D, Flanagan WM, Yakes
• 作者单位：Demirkan B. Gürsel (1)
  Matei A. Banu (1)
  Nicholas Berry (1)
  Roberta Marongiu (2)
  Jan-Karl Burkhardt (1)
  Keith Kobylarz (3)
  Michael G. Kaplitt (2)
  Shahin Rafii (3)
  John A. Boockvar (1)
  
  1. Laboratory for Translational Brain Tumor and Stem Cell Research, Department of Neurological Surgery, Weill Cornell Brain Tumor Center, Weill Cornell Medical College, 525 East 68th Street, Box 99, New York, NY, 10021, USA
  2. Department of Neurological Surgery, Weill Cornell Brain Tumor Center, Weill Cornell Medical College, New York, NY, 10021, USA
  3. Department of Genetic Medicine, Howard Hughes Medical Institute, Ansary Stem Cell Institute, Weill Cornell Medical College, New York, NY, 10021, USA
  
• 刊物类别：Medicine
• 刊物主题：Medicine & Public Health
  Oncology
  
• 出版者：Springer Netherlands
• ISSN：1573-7373

文摘

Malignant gliomas represent one of the most aggressive forms of cancer, displaying high mortality rates and limited treatment options. Specific subpopulations of cells residing in the tumor niche with stem-like characteristics have been postulated to initiate and maintain neoplasticity while resisting conventional therapies. The study presented here aims to define the role of glycogen synthase kinase 3 beta (GSK3b) in patient-derived glioblastoma (GBM) stem-like cell (GSC) proliferation, apoptosis and invasion. To evaluate the potential role of GSK3b in GBM, protein profiles from 68 GBM patients and 20 normal brain samples were analyzed for EGFR-mediated PI3kinase/Akt and GSK3b signaling molecules including protein phosphatase 2A (PP2A). To better understand the function of GSK3b in GBM, GSCs were isolated from GBM patient samples. Blocking GSK3b phosphorylation at Serine 9 attenuated cell proliferation while concomitantly stimulating apoptosis through activation of Caspase-3 in patient-derived GSCs. Increasing GSK3b protein content resulted in the inhibition of cell proliferation, colony formation and stimulated programmed cell death. Depleting GSK3b in GSCs down regulated PP2A. Furthermore, knocking down PP2A or blocking its activity by okadaic acid inactivated GSK3b by increasing GSK3b phosphorylation at Serine 9. Our data suggests that GSK3b may function as a regulator of apoptosis and tumorigenesis in GSCs. Therapeutic approaches targeting GSK3b in glioblastoma stem-like cells may be a useful addition to our current therapeutic armamentarium.