Serine/Threonine Kinase MLK4 Determines Mesenchymal Identity in Glioma Stem Cells in an NFkB-dependent Manner (Cancer Cell 2016;29, 201-213)

報告日期: 2017/03/10
報告時間: 3:10/4:00
報告學生: 劉嬋娟
講評老師: 呂佩融
附件下載: 下載[1636-1487732268-1.pdf] 

Serine/Threonine Kinase MLK4 Determines Mesenchymal Identity in Glioma Stem Cells in an NF-κB-dependent Manner

Cancer Cell (2016) 29: 201-213.

Speaker: Liu Chan-Chuan (劉嬋娟)         Location: Room 602

Commentator: Pei-Jung Lu, Ph.D.         Time: 2017/03/10, 15:10-16:00

The infiltrative-growth gliomas is one of the most lethal brain tumors. Based on the molecular differences, gliomas are classified into proneural (PN), neural, classical (CL), and mesenchymal (MES) by the cancer genome atlas (TCGA) 1. According to current standard of care (SoC), surgery is used to remove the tumor mass, and the following radiation therapy and/or chemotherapy is used to treat infiltrative or residual tumors. Unfortunately,SoC only provides a median survival of only about 15 months2. Gliomas with cancer stem cell properties and phenotype transition are indicated as the reasons of therapeutic failure. With the activity of serine/threonine and tyrosine kinase, mixed lineage kinase 4 (MLK4) is one of MAPK family which can activate JNK, ERK and p383. In this study, the authors investigated the roles of MLK4 in aggressive MES phenotype gliomas with stem cell properties and radioresistance. Compared with CL, neural, and PN gliomas and glioma stem cells (GSCs) among these phenotypes, MLK4 highly expresses in MES gliomas and MES GSCs. Aberrant MLK4 expression reduces MES glioma tumorigenesis. As one of MAP3K family members, MLK4 do not show significant activatory effects on MAPKs. Instead, MLK4 binds to and phosphorylated NF-κB regulator IKKα which is able to form complex with NF-κB inhibitory protein IκB to activate NF-κB signaling. Also, as upstream of NF-κB signaling, block of MLK4 contributes to increment of radiosensitivity of PN gliomas. These findings suggested that MLK4 expression shows inversely correlation with patient prognosis with MES gliomas, and it is required and sufficient for the development of radioresistance in gliomas.

References:

  1. Verhaak, R. G., Hoadley, K. A., Purdom, E., Wang, V., Qi, Y., Wilkerson, M. D., Miller, C. R., Ding, L., Golub, T., Mesirov, J. P., et al. (2010). Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer cell 17, 98-110.
  2. Johnson, D. R., and O'Neill, B. P. (2012). Glioblastoma survival in the United States before and during the temozolomide era. Journal of neuro-oncology 107, 359-364.
  3. Wang, L. H., Besirli, C. G., and Johnson, E. M. J. (2004). Mixed-lineage kinases: A target for the prevention of neurodegeneration. Annu Rev Pharmacol Toxicol 44, 451-474.