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

// Akio Soeda 1 , Justin Lathia 2 , Brian J. Williams 3 , Qiulian Wu 2 , Joseph Gallagher 2 , Andreas Androutsellis-Theotokis 4 , Amber J. Giles 5 , Chunzhang Yang 5 , Zhengping Zhuang 5 , Mark R. Gilbert 5 , Jeremy N. Rich 2 and Deric M. Park 5 1 Department of Neurosurgery, Gifu University, Gifu, Japan 2 Department of Stem Cell Biology and Regenerative Medicine, Cleveland Clinic Foundation, Cleveland, OH, USA 3 Department of Neurosurgery, University of Louisville, Louisville, KY, USA 4 Division of Stem Cell Biology, Technische Universitat Dresden, Dresden, Germany 5 Neuro-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.