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ORP4L is essential for T-cell acute lymphoblastic leukemia cell survival
Metabolic pathways are reprogrammed in cancer to support cell survival. Here, we report that T-cell acute lymphoblastic leukemia (T-ALL) cells are characterized by increased oxidative phosphorylation and robust ATP production. We demonstrate that ORP4L is expressed in T-ALL but not normal T-cells an...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5025801/ https://www.ncbi.nlm.nih.gov/pubmed/27581363 http://dx.doi.org/10.1038/ncomms12702 |
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author | Zhong, Wenbin Yi, Qing Xu, Bing Li, Shiqian Wang, Tong Liu, Fupei Zhu, Biying Hoffmann, Peter R. Ji, Guangju Lei, Pingsheng Li, Guoping Li, Jiwei Li, Jian Olkkonen, Vesa M. Yan, Daoguang |
author_facet | Zhong, Wenbin Yi, Qing Xu, Bing Li, Shiqian Wang, Tong Liu, Fupei Zhu, Biying Hoffmann, Peter R. Ji, Guangju Lei, Pingsheng Li, Guoping Li, Jiwei Li, Jian Olkkonen, Vesa M. Yan, Daoguang |
author_sort | Zhong, Wenbin |
collection | PubMed |
description | Metabolic pathways are reprogrammed in cancer to support cell survival. Here, we report that T-cell acute lymphoblastic leukemia (T-ALL) cells are characterized by increased oxidative phosphorylation and robust ATP production. We demonstrate that ORP4L is expressed in T-ALL but not normal T-cells and its abundance is proportional to cellular ATP. ORP4L acts as an adaptor/scaffold assembling CD3ɛ, Gα(q/11) and PLCβ3 into a complex that activates PLCβ3. PLCβ3 catalyzes IP(3) production in T-ALL as opposed to PLCγ1 in normal T-cells. Up-regulation of ORP4L thus results in a switch in the enzyme responsible for IP(3)-induced endoplasmic reticulum Ca(2+) release and oxidative phosphorylation. ORP4L knockdown results in suboptimal bioenergetics, cell death and abrogation of T-ALL engraftment in vivo. In summary, we uncovered a signalling pathway operating specifically in T-ALL cells in which ORP4L mediates G protein-coupled ligand-induced PLCβ3 activation, resulting in an increase of mitochondrial respiration for cell survival. Targeting ORP4L might represent a promising approach for T-ALL treatment. |
format | Online Article Text |
id | pubmed-5025801 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-50258012016-09-23 ORP4L is essential for T-cell acute lymphoblastic leukemia cell survival Zhong, Wenbin Yi, Qing Xu, Bing Li, Shiqian Wang, Tong Liu, Fupei Zhu, Biying Hoffmann, Peter R. Ji, Guangju Lei, Pingsheng Li, Guoping Li, Jiwei Li, Jian Olkkonen, Vesa M. Yan, Daoguang Nat Commun Article Metabolic pathways are reprogrammed in cancer to support cell survival. Here, we report that T-cell acute lymphoblastic leukemia (T-ALL) cells are characterized by increased oxidative phosphorylation and robust ATP production. We demonstrate that ORP4L is expressed in T-ALL but not normal T-cells and its abundance is proportional to cellular ATP. ORP4L acts as an adaptor/scaffold assembling CD3ɛ, Gα(q/11) and PLCβ3 into a complex that activates PLCβ3. PLCβ3 catalyzes IP(3) production in T-ALL as opposed to PLCγ1 in normal T-cells. Up-regulation of ORP4L thus results in a switch in the enzyme responsible for IP(3)-induced endoplasmic reticulum Ca(2+) release and oxidative phosphorylation. ORP4L knockdown results in suboptimal bioenergetics, cell death and abrogation of T-ALL engraftment in vivo. In summary, we uncovered a signalling pathway operating specifically in T-ALL cells in which ORP4L mediates G protein-coupled ligand-induced PLCβ3 activation, resulting in an increase of mitochondrial respiration for cell survival. Targeting ORP4L might represent a promising approach for T-ALL treatment. Nature Publishing Group 2016-09-01 /pmc/articles/PMC5025801/ /pubmed/27581363 http://dx.doi.org/10.1038/ncomms12702 Text en Copyright © 2016, The Author(s) http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
spellingShingle | Article Zhong, Wenbin Yi, Qing Xu, Bing Li, Shiqian Wang, Tong Liu, Fupei Zhu, Biying Hoffmann, Peter R. Ji, Guangju Lei, Pingsheng Li, Guoping Li, Jiwei Li, Jian Olkkonen, Vesa M. Yan, Daoguang ORP4L is essential for T-cell acute lymphoblastic leukemia cell survival |
title | ORP4L is essential for T-cell acute lymphoblastic leukemia cell survival |
title_full | ORP4L is essential for T-cell acute lymphoblastic leukemia cell survival |
title_fullStr | ORP4L is essential for T-cell acute lymphoblastic leukemia cell survival |
title_full_unstemmed | ORP4L is essential for T-cell acute lymphoblastic leukemia cell survival |
title_short | ORP4L is essential for T-cell acute lymphoblastic leukemia cell survival |
title_sort | orp4l is essential for t-cell acute lymphoblastic leukemia cell survival |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5025801/ https://www.ncbi.nlm.nih.gov/pubmed/27581363 http://dx.doi.org/10.1038/ncomms12702 |
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