Misek Sean A, Chen Jian, Schroeder Laura, Rattanasinchai Chotirat, Sample Ashley, Sarkaria Jann N, Gallo Kathleen A
Department of Physiology, Michigan State University, East Lansing, Michigan.
Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, Michigan.
Mol Cancer Res. 2017 Aug;15(8):1085-1095. doi: 10.1158/1541-7786.MCR-16-0318. Epub 2017 May 9.
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. On the basis of these findings, MLK3 emerges as a potential therapeutic target for the treatment of glioblastoma. .
胶质母细胞瘤（GBM）肿瘤的一个标志是其高度侵袭性行为。肿瘤扩散到周围脑组织会导致手术切除不完全以及随后的肿瘤复发。识别控制GBM细胞扩散的靶点对于开发治疗GBM的有效疗法至关重要。大多数GBM肿瘤存在表皮生长因子受体（EGFR）信号失调，最常见的原因是EGFR扩增或存在组成型活性EGFRvIII突变体。混合系激酶3（MLK3）是一种丝裂原活化蛋白激酶激酶激酶（MAP3K），可激活多种丝裂原活化蛋白激酶（MAPK）途径。在本研究中，有证据表明MLK3对GBM细胞迁移和侵袭至关重要，并且一种MLK抑制剂可阻断表皮生长因子（EGF）诱导的迁移和侵袭。MLK3沉默或MLK抑制可阻断EGF诱导的应激活化蛋白激酶（JNK）激活，这表明MLK3-JNK信号传导促进GBM细胞侵袭。从机制上讲，已证明在侵袭性GBM细胞中过表达的RAC1鸟嘌呤核苷酸交换因子（GEF）DOCK180以RAC1依赖性方式激活MLK3-JNK信号轴。总之，本研究确定了一个驱动胶质母细胞瘤细胞迁移和扩散的EGFR-DOCK180-RAC1-MLK3-JNK信号轴。基于这些发现，MLK3成为治疗胶质母细胞瘤的一个潜在治疗靶点。
