Aberrant mannosylation profile and FTX/miR-342/ALG3-axis contribute to development of drug resistance in acute myeloid leukemia

Drug-resistance is a major problem in acute myeloid leukemia (AML) chemotherapy. Aberrant changes in specific N-glycans have been observed in leukemia multidrug resistance (MDR). MicroRNAs (miRNAs) and long non coding RNAs (lncRNAs) act as key players in the development of AML resistance to chemothe...

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Autores principales: Liu, Bing, Ma, Xiaolu, Liu, Qianqian, Xiao, Yang, Pan, Shimeng, Jia, Li
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5992136/
https://www.ncbi.nlm.nih.gov/pubmed/29880818
http://dx.doi.org/10.1038/s41419-018-0706-7
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author Liu, Bing
Ma, Xiaolu
Liu, Qianqian
Xiao, Yang
Pan, Shimeng
Jia, Li
author_facet Liu, Bing
Ma, Xiaolu
Liu, Qianqian
Xiao, Yang
Pan, Shimeng
Jia, Li
author_sort Liu, Bing
collection PubMed
description Drug-resistance is a major problem in acute myeloid leukemia (AML) chemotherapy. Aberrant changes in specific N-glycans have been observed in leukemia multidrug resistance (MDR). MicroRNAs (miRNAs) and long non coding RNAs (lncRNAs) act as key players in the development of AML resistance to chemotherapy. In the present study, the N-glycan profiles of membrane proteins were analyzed from adriamycin (ADR)-resistant U937/ADR cells and sensitive line U937 cells using mass spectrometry (MS). The composition profiling of high-mannose N-glycans differed in U937/ADR and U937 cell lines. Lectin microarray showed that the strong binding of membrane proteins was observed for MAN-M and ConA lectins, which were specific for mannose. These binding were also validated by flow cytometry. Importantly, the alteration of high-mannose N-glycan was further confirmed by detecting the enzyme level of ALG family. The altered level of ALG3 was found corresponding to the drug-resistant phenotype of AML cell lines both in vitro and in vivo. Mechanistically, miR-342 was found to be dysregulated and inversely correlated to ALG3 expression, targeting its 3′-UTR. LncRNA FTX was a direct target of miR-342 and positively modulated ALG3 expression by competitively binding miR-342 in AML cell lines. Functionally, we found that FTX directly interacted with miR-342 to regulate ALG3 expression and function, including ADR-resistant cell growth and apoptosis. The observation suggested that high-mannose N-glycans and mannosyltransferase ALG3 affected drug-resistance in AML cells. FTX/miR-342/ALG3 axis could potentially be used for the targets to overcome therapeutic resistance in AML.
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spelling pubmed-59921362018-06-08 Aberrant mannosylation profile and FTX/miR-342/ALG3-axis contribute to development of drug resistance in acute myeloid leukemia Liu, Bing Ma, Xiaolu Liu, Qianqian Xiao, Yang Pan, Shimeng Jia, Li Cell Death Dis Article Drug-resistance is a major problem in acute myeloid leukemia (AML) chemotherapy. Aberrant changes in specific N-glycans have been observed in leukemia multidrug resistance (MDR). MicroRNAs (miRNAs) and long non coding RNAs (lncRNAs) act as key players in the development of AML resistance to chemotherapy. In the present study, the N-glycan profiles of membrane proteins were analyzed from adriamycin (ADR)-resistant U937/ADR cells and sensitive line U937 cells using mass spectrometry (MS). The composition profiling of high-mannose N-glycans differed in U937/ADR and U937 cell lines. Lectin microarray showed that the strong binding of membrane proteins was observed for MAN-M and ConA lectins, which were specific for mannose. These binding were also validated by flow cytometry. Importantly, the alteration of high-mannose N-glycan was further confirmed by detecting the enzyme level of ALG family. The altered level of ALG3 was found corresponding to the drug-resistant phenotype of AML cell lines both in vitro and in vivo. Mechanistically, miR-342 was found to be dysregulated and inversely correlated to ALG3 expression, targeting its 3′-UTR. LncRNA FTX was a direct target of miR-342 and positively modulated ALG3 expression by competitively binding miR-342 in AML cell lines. Functionally, we found that FTX directly interacted with miR-342 to regulate ALG3 expression and function, including ADR-resistant cell growth and apoptosis. The observation suggested that high-mannose N-glycans and mannosyltransferase ALG3 affected drug-resistance in AML cells. FTX/miR-342/ALG3 axis could potentially be used for the targets to overcome therapeutic resistance in AML. Nature Publishing Group UK 2018-06-07 /pmc/articles/PMC5992136/ /pubmed/29880818 http://dx.doi.org/10.1038/s41419-018-0706-7 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Liu, Bing
Ma, Xiaolu
Liu, Qianqian
Xiao, Yang
Pan, Shimeng
Jia, Li
Aberrant mannosylation profile and FTX/miR-342/ALG3-axis contribute to development of drug resistance in acute myeloid leukemia
title Aberrant mannosylation profile and FTX/miR-342/ALG3-axis contribute to development of drug resistance in acute myeloid leukemia
title_full Aberrant mannosylation profile and FTX/miR-342/ALG3-axis contribute to development of drug resistance in acute myeloid leukemia
title_fullStr Aberrant mannosylation profile and FTX/miR-342/ALG3-axis contribute to development of drug resistance in acute myeloid leukemia
title_full_unstemmed Aberrant mannosylation profile and FTX/miR-342/ALG3-axis contribute to development of drug resistance in acute myeloid leukemia
title_short Aberrant mannosylation profile and FTX/miR-342/ALG3-axis contribute to development of drug resistance in acute myeloid leukemia
title_sort aberrant mannosylation profile and ftx/mir-342/alg3-axis contribute to development of drug resistance in acute myeloid leukemia
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5992136/
https://www.ncbi.nlm.nih.gov/pubmed/29880818
http://dx.doi.org/10.1038/s41419-018-0706-7
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