EGFRvIII–Stat5 Signaling Enhances Glioblastoma Cell Migration and Survival

Abstract

Glioblastoma multiforme (GBM) is the most common brain malignancies in adults. Most GBM patients succumb to the disease less than 1 year after diagnosis due to the highly invasive nature of the tumor, which prevents complete surgical resection and gives rise to tumor recurrence. The invasive phenotype also confers radioresistant and chemoresistant properties to the tumor cells; therefore, there is a critical need to develop new therapeutics that target drivers of GBM invasion. Amplification of EGFR is observed in over 50% of GBM tumors, of which half concurrently overexpress the variant EGFRvIII, and expression of both receptors confers a worse prognosis. EGFR and EGFRvIII cooperate to promote tumor progression and invasion, in part, through activation of the Stat signaling pathway. Here, it is reported that EGFRvIII activates Stat5 and GBM invasion by inducing the expression of a previously established mediator of glioma cell invasion and survival: fibroblast growth factor-inducible 14 (Fn14). EGFRvIII-mediated induction of Fn14 expression is Stat5 dependent and requires activation of Src, whereas EGFR regulation of Fn14 is dependent upon Src-MEK/ERK-Stat3 activation. Notably, treatment of EGFRvIII-expressing GBM cells with the FDA-approved Stat5 inhibitor pimozide blocked Stat5 phosphorylation, Fn14 expression, and cell migration and survival. Because EGFR inhibitors display limited therapeutic efficacy in GBM patients, the EGFRvIII-Stat5-Fn14 signaling pathway represents a node of vulnerability in the invasive GBM cell populations. Targeting critical effectors in the EGFRvIII-Stat5-Fn14 pathway may limit GBM tumor dispersion, mitigate therapeutic resistance, and increase survival. .

Aberrant Activation of hsa-miR-181d/STAT3 and hsa-miR-181d/5A Ratios Mediate the Anticancer Effect of Garcinol in STAT3/5A-Addicted GBM

“…STAT3 and STAT5 are transcription factors implicated in various tumor cell proliferation, migration, and invasion (Roos et al, 2018). STAT3 and STAT5A in response to cytokines and growth factors are activated by phosphorylation of their Y705 position and Y695 residues, respectively, followed by nuclear translocation of the phosphorylated proteins with subsequent activation of specific downstream gene transcription (Mohanty et al, 2017).…”

“…Activation of STAT3 and STAT5 serve different purposes. STAT3 has been shown to promote the proliferation and pathobiology of GBM tumor cores, while STAT5 affects its local invasion capabilities (Roos et al, 2018). Evidence also abound that STAT3 signaling plays a role in maintaining the self-renewal capabilities and multilineage differentiation potential of glioma stem cells (GSMs) (Guryanova et al, 2011).…”

“…Firstly, against the background that STAT3 and STAT5 to be highly expressed in GBM cell lines (Roos et al, 2018), we evaluated the expression profiles of STAT proteins GDC TCGA-GBM cohort of 173 samples. Our results showed a 1.07-fold or 1.08-fold increase in the median gene expression of STAT3 in the primary and recurrent GBM samples, respectively, compared to non-tumor samples;…”

“…Li et al demonstrated that lentivirus-mediated silencing STAT3 in GBM cells induces cellular differentiation, indicating its role in keeping an undifferentiated cellular state in malignancy (G. Li et al, 2009). As with STAT3, STAT5A is a key effector of the Janus Tyrosine Kinase (JAK)/STAT pathway, its phosphorylation being positively correlated with cell invasion and poor prognosis in GBM (Cao et al, 2011;Latha et al, 2013;Roos et al, 2018). Fan et al demonstrated that STAT5 signaling drives pro-tumorigenic phenotypes in GBM cells (Fan et al, 2013).…”

Glioblastoma Multiforme Stem Cell Cycle Arrest by Alkylaminophenol through the Modulation of EGFR and CSC Signaling Pathways

“…In addition to the CSC signaling pathways, EGFR signaling is also reported as a primary contributor to GBM initiation and progression. Oncogenic role of EGFR driving to GBM tumorigenesis has been validated both in in vivo and in vitro models [15][16][17][18][19]. Thus, targeting important downstream signaling pathways in CSC is important for identifying novel GBM therapy.…”