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. Here...
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doaj-48c32b7ce9c84250b8c43965785dfaee2020-11-25T02:50:28ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662020-08-0139111810.1186/s13046-020-01658-zTNFAIP8 promotes AML chemoresistance by activating ERK signaling pathway through interaction with Rac1Yihua Pang0Yanan Zhao1Yan Wang2Xinlu Wang3Ruiqing Wang4Na Liu5Peng Li6Min Ji7Jingjing Ye8Tao Sun9Jingxin Li10Daoxin Ma11Fei Lu12Chunyan Ji13Department of Hematology, Qilu Hospital of Shandong UniversityDepartment of Hematology, Qilu Hospital of Shandong UniversityDepartment of Hematology, Taian central hospitalDepartment of Hematology, Qilu Hospital of Shandong UniversityDepartment of Hematology, Qilu Hospital of Shandong UniversityDepartment of Hematology, Qilu Hospital of Shandong UniversityDepartment of Hematology, Qilu Hospital of Shandong UniversityDepartment of Hematology, Qilu Hospital of Shandong UniversityDepartment of Hematology, Qilu Hospital of Shandong UniversityDepartment of Hematology, Qilu Hospital of Shandong UniversityDepartment of Physiology, School of Basic Medical Sciences, Shandong UniversityDepartment of Hematology, Qilu Hospital of Shandong UniversityDepartment of Hematology, Qilu Hospital of Shandong UniversityDepartment of Hematology, Qilu Hospital of Shandong UniversityAbstract 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.http://link.springer.com/article/10.1186/s13046-020-01658-zTNFAIP8ApoptosisChemoresistanceERKRac1AML |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
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 |
spellingShingle |
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 TNFAIP8 promotes AML chemoresistance by activating ERK signaling pathway through interaction with Rac1 Journal of Experimental & Clinical Cancer Research TNFAIP8 Apoptosis Chemoresistance ERK Rac1 AML |
author_facet |
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 |
author_sort |
Yihua Pang |
title |
TNFAIP8 promotes AML chemoresistance by activating ERK signaling pathway through interaction with Rac1 |
title_short |
TNFAIP8 promotes AML chemoresistance by activating ERK signaling pathway through interaction with Rac1 |
title_full |
TNFAIP8 promotes AML chemoresistance by activating ERK signaling pathway through interaction with Rac1 |
title_fullStr |
TNFAIP8 promotes AML chemoresistance by activating ERK signaling pathway through interaction with Rac1 |
title_full_unstemmed |
TNFAIP8 promotes AML chemoresistance by activating ERK signaling pathway through interaction with Rac1 |
title_sort |
tnfaip8 promotes aml chemoresistance by activating erk signaling pathway through interaction with rac1 |
publisher |
BMC |
series |
Journal of Experimental & Clinical Cancer Research |
issn |
1756-9966 |
publishDate |
2020-08-01 |
description |
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. |
topic |
TNFAIP8 Apoptosis Chemoresistance ERK Rac1 AML |
url |
http://link.springer.com/article/10.1186/s13046-020-01658-z |
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