TNFAIP8 promotes AML chemoresistance by activating ERK signaling pathway through interaction with Rac1.

Publisher: BioMed Central Country of Publication: England NLM ID: 8308647 Publication Model: Electronic Cited Medium: Internet ISSN: 1756-9966 (Electronic) Linking ISSN: 03929078 NLM ISO Abbreviation: J Exp Clin Cancer Res Subsets: MEDLINE

Publication: 2009- : London : BioMed Central
Original Publication: [Roma] : APSIT,

Drug Resistance, Neoplasm*; Antineoplastic Agents/*pharmacology ; Apoptosis Regulatory Proteins/*metabolism ; Leukemia, Myeloid, Acute/*drug therapy ; Mitogen-Activated Protein Kinase 1/*metabolism ; Mitogen-Activated Protein Kinase 3/*metabolism ; rac1 GTP-Binding Protein/*metabolism; Adolescent ; Adult ; Aged ; Animals ; Apoptosis ; Apoptosis Regulatory Proteins/genetics ; Biomarkers, Tumor/genetics ; Biomarkers, Tumor/metabolism ; Case-Control Studies ; Cell Movement ; Cell Proliferation ; Female ; Gene Expression Regulation, Neoplastic ; Humans ; Leukemia, Myeloid, Acute/metabolism ; Leukemia, Myeloid, Acute/pathology ; Mice ; Mice, Inbred C57BL ; Middle Aged ; Mitogen-Activated Protein Kinase 1/genetics ; Mitogen-Activated Protein Kinase 3/genetics ; Prognosis ; Signal Transduction ; Tumor Cells, Cultured ; Xenograft Model Antitumor Assays ; Young Adult ; rac1 GTP-Binding Protein/genetics

Background: Chemoresistance is emerging as a major barrier to successful treatment in acute myeloid leukemia (AML), and evasion of apoptosis is among the fundamental underlying mechanisms. Therefore, unraveling molecular networks that drive this process constitutes an urgent unmet need. Herein, we aim to characterize the role and molecular mechanism of the tumor necrosis factor ɑ-induced protein 8 (TNFAIP8), a novel anti-apoptotic molecule, in AML chemoresistance.
Methods: The expression levels of TNFAIP8 were assessed in AML patients and cell lines by RT-qPCR and western blots. The transcriptional regulation of TNFAIP8 was analyzed with luciferase reporter assay and ChIP followed by RT-qPCR. Functional experiments were conducted to evaluate the effects of TNFAIP8 on apoptosis, drug sensitivity and proliferation of AML cells. Potential effects of TNFAIP8 on the activation of extracellular signal-regulated kinase (ERK) pathway were detected by western blots. CoIP and P21-activated kinase (PAK) pull-down assay were performed to ascertain the upstream target. The overall effects of TNFAIP8 on AML were examined in murine models.
Results: Upregulated TNFAIP8 expression was first confirmed in human AML patients and cell lines. E74 like ETS transcription factor 1 (ELF1) was then identified to contribute to its aberrant expression. Through manipulating TNFAIP8 expression, we described its role in protecting AML cells from apoptosis induced by chemotherapeutic agents and in promoting drug resistance. Notably, the leukemia-promoting action of TNFAIP8 was mediated by sustaining activity of the ERK signaling pathway, through an interaction with Rac family small GTPase 1 (Rac1). In addition, in vivo experiments confirmed that TNFAIP8 suppression lowered leukemia infiltration and improved survival.
Conclusion: Our data provide a molecular basis for the role of TNFAIP8 in chemoresistance and progression of AML and highlight the unique function of TNFAIP8 as an attractive therapeutic target.

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2018CXGC1215 grants from Major Science and Technology Innovation Project of Shandong Province; 81770159 National Natural Science Foundation of China; 81500130 National Natural Science Foundation of China; 81600124 National Natural Science Foundation of China; 2018GSF118014 Key Research and Development Program of Shandong Province; 2017G006015 Key Research and Development Program of Shandong Province; 2018JC003 The Fundamental Research Funds of Shandong University; 2017JC015 The Fundamental Research Funds of Shandong University; 81700143 National Natural Science Foundation of China; 81873425 National Natural Science Foundation of China

Keywords: AML; Apoptosis; Chemoresistance; ERK; Rac1; TNFAIP8

0 (Antineoplastic Agents)
0 (Apoptosis Regulatory Proteins)
0 (Biomarkers, Tumor)
0 (RAC1 protein, human)
0 (TNFAIP8 protein, human)
EC 2.7.11.24 (MAPK1 protein, human)
EC 2.7.11.24 (MAPK3 protein, human)
EC 2.7.11.24 (Mitogen-Activated Protein Kinase 1)
EC 2.7.11.24 (Mitogen-Activated Protein Kinase 3)
EC 3.6.5.2 (rac1 GTP-Binding Protein)

Date Created: 20200816 Date Completed: 20210427 Latest Revision: 20210427

20221213

PMC7427779

10.1186/s13046-020-01658-z

32795319