Cargando…

The role of PKM2 nuclear translocation in the constant activation of the NF-κB signaling pathway in cancer-associated fibroblasts

Cancer-associated fibroblasts (CAFs) play critical roles in cancer progression by regulating tumor cell proliferation, angiogenesis, and metastasis. Recent studies demonstrated that CAFs induce inhibitory immune cell infiltration and chemotherapy resistance in gastric cancer by activating the NF-κB...

Descripción completa

Detalles Bibliográficos
Autores principales: Gu, Junjie, Li, Xuechun, Zhao, Lin, Yang, Ying, Xue, Chunling, Gao, Yang, Li, Jing, Han, Qin, Sun, Zhao, Bai, Chunmei, Zhao, Robert Chunhua
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7969736/
https://www.ncbi.nlm.nih.gov/pubmed/33731686
http://dx.doi.org/10.1038/s41419-021-03579-x
_version_ 1783666286345060352
author Gu, Junjie
Li, Xuechun
Zhao, Lin
Yang, Ying
Xue, Chunling
Gao, Yang
Li, Jing
Han, Qin
Sun, Zhao
Bai, Chunmei
Zhao, Robert Chunhua
author_facet Gu, Junjie
Li, Xuechun
Zhao, Lin
Yang, Ying
Xue, Chunling
Gao, Yang
Li, Jing
Han, Qin
Sun, Zhao
Bai, Chunmei
Zhao, Robert Chunhua
author_sort Gu, Junjie
collection PubMed
description Cancer-associated fibroblasts (CAFs) play critical roles in cancer progression by regulating tumor cell proliferation, angiogenesis, and metastasis. Recent studies demonstrated that CAFs induce inhibitory immune cell infiltration and chemotherapy resistance in gastric cancer by activating the NF-κB signaling pathway to secrete IL6, IL8, and other inflammatory factors. Inhibition of the NF-κB signaling pathway in CAFs might be a potential therapeutic strategy in gastric cancer. However, how the NF-κB pathway is activated in CAFs remains unclear. We showed that mesenchymal stem cells (MSCs) differentiated into CAFs, induced by the exosomes derived from gastric cancer cells. During the process of differentiation from MSCs into CAFs, we showed that nuclear PKM2 expression was continuously upregulated and associated with NF-κB P65 acetylation, contributing to P65 nuclear retention in CAFs and constant transcription of IL-6, IL-8, and other inflammatory factors, thus promoting gastric cancer cell proliferation. We showed that NF-κB P65 acetylation was induced by P300. We showed that nuclear PKM2 was derived from exosomes of gastric cancer cell lines and the positive feedback loop induced by PKM2-P65 combination. It is also proved that P300 inhibitors can inhibit tumor proliferation in an AGS subcutaneous xenograft tumor model. Our study showed that gastric cancer cells influence the continuous activation of the NF-κB signaling pathway in CAFs by secreting gastric cancer exosomes containing PKM2, thus inducing abnormal metabolism and inflammation activation. This study provides a new therapeutic target for CAF normalization or deactivation strategies.
format Online
Article
Text
id pubmed-7969736
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher Nature Publishing Group UK
record_format MEDLINE/PubMed
spelling pubmed-79697362021-04-01 The role of PKM2 nuclear translocation in the constant activation of the NF-κB signaling pathway in cancer-associated fibroblasts Gu, Junjie Li, Xuechun Zhao, Lin Yang, Ying Xue, Chunling Gao, Yang Li, Jing Han, Qin Sun, Zhao Bai, Chunmei Zhao, Robert Chunhua Cell Death Dis Article Cancer-associated fibroblasts (CAFs) play critical roles in cancer progression by regulating tumor cell proliferation, angiogenesis, and metastasis. Recent studies demonstrated that CAFs induce inhibitory immune cell infiltration and chemotherapy resistance in gastric cancer by activating the NF-κB signaling pathway to secrete IL6, IL8, and other inflammatory factors. Inhibition of the NF-κB signaling pathway in CAFs might be a potential therapeutic strategy in gastric cancer. However, how the NF-κB pathway is activated in CAFs remains unclear. We showed that mesenchymal stem cells (MSCs) differentiated into CAFs, induced by the exosomes derived from gastric cancer cells. During the process of differentiation from MSCs into CAFs, we showed that nuclear PKM2 expression was continuously upregulated and associated with NF-κB P65 acetylation, contributing to P65 nuclear retention in CAFs and constant transcription of IL-6, IL-8, and other inflammatory factors, thus promoting gastric cancer cell proliferation. We showed that NF-κB P65 acetylation was induced by P300. We showed that nuclear PKM2 was derived from exosomes of gastric cancer cell lines and the positive feedback loop induced by PKM2-P65 combination. It is also proved that P300 inhibitors can inhibit tumor proliferation in an AGS subcutaneous xenograft tumor model. Our study showed that gastric cancer cells influence the continuous activation of the NF-κB signaling pathway in CAFs by secreting gastric cancer exosomes containing PKM2, thus inducing abnormal metabolism and inflammation activation. This study provides a new therapeutic target for CAF normalization or deactivation strategies. Nature Publishing Group UK 2021-03-17 /pmc/articles/PMC7969736/ /pubmed/33731686 http://dx.doi.org/10.1038/s41419-021-03579-x Text en © The Author(s) 2021 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
Gu, Junjie
Li, Xuechun
Zhao, Lin
Yang, Ying
Xue, Chunling
Gao, Yang
Li, Jing
Han, Qin
Sun, Zhao
Bai, Chunmei
Zhao, Robert Chunhua
The role of PKM2 nuclear translocation in the constant activation of the NF-κB signaling pathway in cancer-associated fibroblasts
title The role of PKM2 nuclear translocation in the constant activation of the NF-κB signaling pathway in cancer-associated fibroblasts
title_full The role of PKM2 nuclear translocation in the constant activation of the NF-κB signaling pathway in cancer-associated fibroblasts
title_fullStr The role of PKM2 nuclear translocation in the constant activation of the NF-κB signaling pathway in cancer-associated fibroblasts
title_full_unstemmed The role of PKM2 nuclear translocation in the constant activation of the NF-κB signaling pathway in cancer-associated fibroblasts
title_short The role of PKM2 nuclear translocation in the constant activation of the NF-κB signaling pathway in cancer-associated fibroblasts
title_sort role of pkm2 nuclear translocation in the constant activation of the nf-κb signaling pathway in cancer-associated fibroblasts
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7969736/
https://www.ncbi.nlm.nih.gov/pubmed/33731686
http://dx.doi.org/10.1038/s41419-021-03579-x
work_keys_str_mv AT gujunjie theroleofpkm2nucleartranslocationintheconstantactivationofthenfkbsignalingpathwayincancerassociatedfibroblasts
AT lixuechun theroleofpkm2nucleartranslocationintheconstantactivationofthenfkbsignalingpathwayincancerassociatedfibroblasts
AT zhaolin theroleofpkm2nucleartranslocationintheconstantactivationofthenfkbsignalingpathwayincancerassociatedfibroblasts
AT yangying theroleofpkm2nucleartranslocationintheconstantactivationofthenfkbsignalingpathwayincancerassociatedfibroblasts
AT xuechunling theroleofpkm2nucleartranslocationintheconstantactivationofthenfkbsignalingpathwayincancerassociatedfibroblasts
AT gaoyang theroleofpkm2nucleartranslocationintheconstantactivationofthenfkbsignalingpathwayincancerassociatedfibroblasts
AT lijing theroleofpkm2nucleartranslocationintheconstantactivationofthenfkbsignalingpathwayincancerassociatedfibroblasts
AT hanqin theroleofpkm2nucleartranslocationintheconstantactivationofthenfkbsignalingpathwayincancerassociatedfibroblasts
AT sunzhao theroleofpkm2nucleartranslocationintheconstantactivationofthenfkbsignalingpathwayincancerassociatedfibroblasts
AT baichunmei theroleofpkm2nucleartranslocationintheconstantactivationofthenfkbsignalingpathwayincancerassociatedfibroblasts
AT zhaorobertchunhua theroleofpkm2nucleartranslocationintheconstantactivationofthenfkbsignalingpathwayincancerassociatedfibroblasts
AT gujunjie roleofpkm2nucleartranslocationintheconstantactivationofthenfkbsignalingpathwayincancerassociatedfibroblasts
AT lixuechun roleofpkm2nucleartranslocationintheconstantactivationofthenfkbsignalingpathwayincancerassociatedfibroblasts
AT zhaolin roleofpkm2nucleartranslocationintheconstantactivationofthenfkbsignalingpathwayincancerassociatedfibroblasts
AT yangying roleofpkm2nucleartranslocationintheconstantactivationofthenfkbsignalingpathwayincancerassociatedfibroblasts
AT xuechunling roleofpkm2nucleartranslocationintheconstantactivationofthenfkbsignalingpathwayincancerassociatedfibroblasts
AT gaoyang roleofpkm2nucleartranslocationintheconstantactivationofthenfkbsignalingpathwayincancerassociatedfibroblasts
AT lijing roleofpkm2nucleartranslocationintheconstantactivationofthenfkbsignalingpathwayincancerassociatedfibroblasts
AT hanqin roleofpkm2nucleartranslocationintheconstantactivationofthenfkbsignalingpathwayincancerassociatedfibroblasts
AT sunzhao roleofpkm2nucleartranslocationintheconstantactivationofthenfkbsignalingpathwayincancerassociatedfibroblasts
AT baichunmei roleofpkm2nucleartranslocationintheconstantactivationofthenfkbsignalingpathwayincancerassociatedfibroblasts
AT zhaorobertchunhua roleofpkm2nucleartranslocationintheconstantactivationofthenfkbsignalingpathwayincancerassociatedfibroblasts