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

Abstract

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.

• Authors: Yihua Pang, Yanan Zhao, Yan Wang, Xinlu Wang, Ruiqing Wang, Na Liu, Peng Li, Min Ji, Jingjing Ye, Tao Sun, Jingxin Li, Daoxin Ma, Fei Lu, Chunyan Ji
• Journal: Journal of experimental & clinical cancer research : CR (J Exp Clin Cancer Res) Vol. 39 Issue 1 Pg. 158 (Aug 14 2020) ISSN: 1756-9966 [Electronic] England
• PMID: 32795319 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Apoptosis Regulatory Proteins
• Biomarkers, Tumor
• RAC1 protein, human
• TNFAIP8 protein, human
• MAPK1 protein, human
• MAPK3 protein, human
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3
• rac1 GTP-Binding Protein

Topics

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