Oncotarget

Research Papers:

The p38 signaling pathway mediates quiescence of glioma stem cells by regulating epidermal growth factor receptor trafficking

Akio Soeda, Justin Lathia, Brian J. Williams, Qiulian Wu, Joseph Gallagher, Andreas Androutsellis-Theotokis, Amber J. Giles, Chunzhang Yang, Zhengping Zhuang, Mark R. Gilbert, Jeremy N. Rich and Deric M. Park _

PDF  |  HTML  |  Supplementary Files  |  How to cite  |  Order a Reprint

Oncotarget. 2017; 8:33316-33328. https://doi.org/10.18632/oncotarget.16741

Metrics: PDF 1473 views  |   HTML 1986 views  |   ?  


Abstract

Akio Soeda1, Justin Lathia2, Brian J. Williams3, Qiulian Wu2, Joseph Gallagher2, Andreas Androutsellis-Theotokis4, Amber J. Giles5, Chunzhang Yang5, Zhengping Zhuang5, Mark R. Gilbert5, Jeremy N. Rich2 and Deric M. Park5

1Department of Neurosurgery, Gifu University, Gifu, Japan

2Department of Stem Cell Biology and Regenerative Medicine, Cleveland Clinic Foundation, Cleveland, OH, USA

3Department of Neurosurgery, University of Louisville, Louisville, KY, USA

4Division of Stem Cell Biology, Technische Universitat Dresden, Dresden, Germany

5Neuro-Oncology Branch, National Cancer Institute, NIH, Bethesda, MD, USA

Correspondence to:

Deric M. Park, email: deric.park@nih.gov

Keywords: glioma, cancer stem cell, p38 MAPK, EGFR, quiescence

Received: July 10, 2016     Accepted: March 19, 2017     Published: March 31, 2017

ABSTRACT

EGFR pathway is upregulated in malignant gliomas, and its downstream signaling is important for self-renewal of glioma cancer stem-like cells (GSC). p38 mitogen-activated protein kinase (MAPK) signaling, a stress-activated signaling cascade with suppressive and permissive effects on tumorigenesis, can promote internalization and ubiquitin ligase mediated degradation of EGFR. In this study, we investigated the role of p38 MAPK signaling on the self-renewal of GSCs with the hypothesis that inhibition may lead to enhanced self-renewal capacity by retention of EGFR. Inhibition of p38 MAPK pathway led to increase in EGFR expression but surprisingly, reduced proliferation. Additional functional evaluation revealed that p38 inhibition was associated with decrease in cell death and maintenance of undifferentiated state. Further probing the effect of p38 inhibition demonstrated attenuation of EGFR downstream signaling activity in spite of prolonged surface expression of the receptor. In vitro observations were confirmed in xenograft in vivo experiments. These data suggest that p38 MAPK control of EGFR signaling activity may alter GSC cell cycle state by regulating quiescence and passage into transit amplifying state.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
PII: 16741