Abstract
A hallmark of glioblastoma (GBM) tumors is their highly invasive behavior. Tumor dissemination into surrounding brain tissue is responsible for incomplete surgical resection, and subsequent tumor recurrence. Identification of targets that control GBM cell dissemination is critical for developing effective therapies to treat GBM. A majority of GBM tumors have dysregulated EGFR signaling, due most frequently to EGFR amplification or the presence of a constitutively active EGFRvIII mutant. Mixed lineage kinase 3 (MLK3) is a mitogen-activated protein kinase kinase kinase (MAP3K) that can activate multiple MAPK pathways. In this study, evidence is provided that MLK3 is essential for GBM cell migration and invasion, and that an MLK inhibitor blocks EGF-induced migration and invasion. MLK3 silencing or MLK inhibition blocks EGF-induced JNK activation, suggesting that MLK3-JNK signaling promotes invasion of GBM cells. Mechanistically, it is demonstrated that DOCK180, a RAC1 guanine nucleotide exchange factor (GEF) overexpressed in invasive GBM cells, activates the MLK3-JNK signaling axis in a RAC1-dependent manner. In summary, this investigation identifies an EGFR-DOCK180-RAC1-MLK3-JNK signaling axis that drives glioblastoma cell migration and dissemination.Implications: On the basis of these findings, MLK3 emerges as a potential therapeutic target for the treatment of glioblastoma. Mol Cancer Res; 15(8); 1085-95. ©2017 AACR.
Highlights
Glioblastoma (GBM) tumors are the deadliest of adult brain tumors
Mixed lineage kinase 3 (MLK3) is required for glioblastoma cell migration MLK3 expression was detected by immunoblotting in a panel of human GBM cell lines, as well as in normal human astrocytes (NHA)
Because DOCK180 is a RAC1-specific guanine nucleotide exchange factor (GEF) that drives glioma progression [11], and because Rac can activate MLK3 signaling to JNK [12, 17], we examined whether DOCK180 silencing could affect JNK signaling in GBM cells
Summary
Glioblastoma (GBM) tumors are the deadliest of adult brain tumors. Invasion of GBM tumor cells into the surrounding brain leads to tumor relapse, and a dismal patient prognosis. Even with recent treatment advances in surgery, radiotherapy, antiangiogenic therapies, and temozolomide regimens, the average survival time of patients with GBM is typically 12 to 15 months [1]. Substantial evidence suggests that angiogenesis inhibitors and radiotherapy may promote tumor invasion [2]. The signaling pathways required for GBM cell migration and invasion are not fully delineated. Characterization of the mechanisms that drive GBM cell dissemination may lead to the identification of novel therapeutic targets
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