MAP4K4 promotes pancreatic tumorigenesis via phosphorylation and activation of mixed lineage kinase 3
Open Access
- 13 September 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Oncogene
- Vol. 40 (43), 6153-6165
- https://doi.org/10.1038/s41388-021-02007-w
Abstract
MAP4K4 is a Ste20 member and reported to play important roles in various pathologies, including in cancer. However, the mechanism by which MAP4K4 promotes pancreatic cancer is not fully understood. It is suggested that MAP4K4 might function as a cancer promoter via specific downstream target(s) in an organ-specific manner. Here we identified MLK3 as a direct downstream target of MAP4K4. The MAP4K4 and MLK3 associates with each other, and MAP4K4 phosphorylates MLK3 on Thr738 and increases MLK3 kinase activity and downstream signaling. The phosphorylation of MLK3 by MAP4K4 promotes pancreatic cancer cell proliferation, migration, and colony formation. Moreover, MAP4K4 is overexpressed in human pancreatic tumors and directly correlates with the disease progression. The MAP4K4-specific pharmacological inhibitor, GNE-495, impedes pancreatic cancer cell growth, migration, induces cell death, and arrests cell cycle progression. Additionally, the GNE-495 reduced the tumor burden and extended survival of the KPC mice with pancreatic cancer. The MAP4K4 inhibitor also reduced MAP4K4 protein expression, tumor stroma, and induced cell death in murine pancreatic tumors. These findings collectively suggest that MLK3 phosphorylation by MAP4K4 promotes pancreatic cancer, and therefore therapies targeting MAP4K4 might alleviate the pancreatic cancer tumor burden in patients.Funding Information
- U.S. Department of Veterans Affairs (BX004903, BX004855, BX003296)
- U.S. Department of Health & Human Services | NIH | National Cancer Institute (CA216410, CA176846, CA236031, F30-CA236031, CA178063, CA219764)
- U.S. Department of Health & Human Services | NIH | National Cancer Institute
- U.S. Department of Health & Human Services | NIH | National Cancer Institute
- U.S. Department of Health & Human Services | NIH | National Cancer Institute
- U.S. Department of Health & Human Services | NIH | National Cancer Institute
- U.S. Department of Health & Human Services | NIH | National Cancer Institute
This publication has 44 references indexed in Scilit:
- Novel Pancreatic Cancer Cell Lines Derived from Genetically Engineered Mouse Models of Spontaneous Pancreatic Adenocarcinoma: Applications in Diagnosis and TherapyPLOS ONE, 2013
- Mixed-lineage kinase 3 phosphorylates prolyl-isomerase Pin1 to regulate its nuclear translocation and cellular functionProceedings of the National Academy of Sciences of the United States of America, 2012
- Estrogen Suppresses MLK3-Mediated Apoptosis Sensitivity in ER+ Breast Cancer CellsCancer Research, 2010
- Orally delivered siRNA targeting macrophage Map4k4 suppresses systemic inflammationNature, 2009
- Expression of MAP4K4 Is Associated with Worse Prognosis in Patients with Stage II Pancreatic Ductal AdenocarcinomaClinical Cancer Research, 2008
- Anti–Tumor Necrosis Factor Therapy Inhibits Pancreatic Tumor Growth and MetastasisCancer Research, 2008
- Scaffold proteins of MAP-kinase modulesOncogene, 2007
- The STE20 Kinase HGK Is Broadly Expressed in Human Tumor Cells and Can Modulate Cellular Transformation, Invasion, and AdhesionMolecular and Cellular Biology, 2003
- Activation of the Drosophila MLK by Ceramide Reveals TNF-α and Ceramide as Agonists of Mammalian MLK3Molecular Cell, 2002
- CEP-1347 (KT7515), a Semisynthetic Inhibitor of the Mixed Lineage Kinase FamilyOnline Journal of Public Health Informatics, 2001