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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.
Highlights
Glioblastoma (GBM) is an incurable brain cancer with a median survival of approximately one year with multimodal treatment consisting of surgery, irradiation, and chemotherapy [1]
We found basal activation of the p38 mitogenactivated protein kinase (MAPK) pathway in glioma cancer stem-like cells (GSC); the level of p38 activation did not change with addition of exogenous epidermal growth factor (EGF) suggesting that the basal activation state of p38 is not regulated by mitogenic signaling (Figure 1A and Supplementary Figure 3)
Given previous reports www.impactjournals.com/oncotarget demonstrating interaction of epidermal growth factor receptor (EGFR) and p38 MAPK pathways, and the importance of EGFR signaling on the self-renewal of GSC, we investigated the role of p38 pathway in GSC
Summary
Glioblastoma (GBM) is an incurable brain cancer with a median survival of approximately one year with multimodal treatment consisting of surgery, irradiation, and chemotherapy [1]. It has been reported that GSC demonstrate exquisite sensitivity to inhibition of the Akt pathway, a serine/threonine-specific protein kinase that regulates cellular growth-survival pathways downstream of receptor tyrosine kinases [10]. One such example of a receptor tyrosine kinase that is frequently altered in a variety of cancers including GBM is the epidermal growth factor receptor (EGFR), a member of the ErbB family of receptor tyrosine kinases [11]. A key tumorigenic event in the pathogenesis of GBM consists of activating disruption of the EGFR by mutation and amplification [13]
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