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Extracellular PKM2 facilitates organ-tissue fibrosis progression
Persistent activation of fibroblasts and resistance of myofibroblasts to turnover play important roles in organ-tissue fibrosis development and progression. The mechanism that mediates apoptosis resistance of myofibroblasts is not understood. Here, we report that myofibroblasts express and secrete P...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8517170/ https://www.ncbi.nlm.nih.gov/pubmed/34693222 http://dx.doi.org/10.1016/j.isci.2021.103165 |
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author | Han, Hongwei Zhang, Yinwei Peng, Guangda Li, Liangwei Yang, Jenny Yuan, Yi Xu, Yiting Liu, Zhi-Ren |
author_facet | Han, Hongwei Zhang, Yinwei Peng, Guangda Li, Liangwei Yang, Jenny Yuan, Yi Xu, Yiting Liu, Zhi-Ren |
author_sort | Han, Hongwei |
collection | PubMed |
description | Persistent activation of fibroblasts and resistance of myofibroblasts to turnover play important roles in organ-tissue fibrosis development and progression. The mechanism that mediates apoptosis resistance of myofibroblasts is not understood. Here, we report that myofibroblasts express and secrete PKM2. Extracellular PKM2 (EcPKM2) facilitates progression of fibrosis by protecting myofibroblasts from apoptosis. EcPKM2 upregulates arginase-1 expression in myofibroblasts and therefore facilitates proline biosynthesis and subsequent collagen production. EcPKM2 interacts with integrin α(v)β(3) on myofibroblasts to activate FAK-PI3K signaling axis. Activation of FAK-PI3K by EcPKM2 activates downstream NF-κB survival pathway to prevent myofibroblasts from apoptosis. On the other hand, activation of FAK- PI3K by EcPKM2 suppresses PTEN to subsequently upregulate arginase-1 in myofibroblasts. Our studies uncover an important mechanism for organ fibrosis progression. More importantly, an antibody disrupting the interaction between PKM2 and integrin α(v)β(3) is effective in reversing fibrosis, suggesting a possible therapeutic strategy and target for treatment of organ fibrosis. |
format | Online Article Text |
id | pubmed-8517170 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-85171702021-10-21 Extracellular PKM2 facilitates organ-tissue fibrosis progression Han, Hongwei Zhang, Yinwei Peng, Guangda Li, Liangwei Yang, Jenny Yuan, Yi Xu, Yiting Liu, Zhi-Ren iScience Article Persistent activation of fibroblasts and resistance of myofibroblasts to turnover play important roles in organ-tissue fibrosis development and progression. The mechanism that mediates apoptosis resistance of myofibroblasts is not understood. Here, we report that myofibroblasts express and secrete PKM2. Extracellular PKM2 (EcPKM2) facilitates progression of fibrosis by protecting myofibroblasts from apoptosis. EcPKM2 upregulates arginase-1 expression in myofibroblasts and therefore facilitates proline biosynthesis and subsequent collagen production. EcPKM2 interacts with integrin α(v)β(3) on myofibroblasts to activate FAK-PI3K signaling axis. Activation of FAK-PI3K by EcPKM2 activates downstream NF-κB survival pathway to prevent myofibroblasts from apoptosis. On the other hand, activation of FAK- PI3K by EcPKM2 suppresses PTEN to subsequently upregulate arginase-1 in myofibroblasts. Our studies uncover an important mechanism for organ fibrosis progression. More importantly, an antibody disrupting the interaction between PKM2 and integrin α(v)β(3) is effective in reversing fibrosis, suggesting a possible therapeutic strategy and target for treatment of organ fibrosis. Elsevier 2021-09-25 /pmc/articles/PMC8517170/ /pubmed/34693222 http://dx.doi.org/10.1016/j.isci.2021.103165 Text en © 2021 The Author(s) https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Article Han, Hongwei Zhang, Yinwei Peng, Guangda Li, Liangwei Yang, Jenny Yuan, Yi Xu, Yiting Liu, Zhi-Ren Extracellular PKM2 facilitates organ-tissue fibrosis progression |
title | Extracellular PKM2 facilitates organ-tissue fibrosis progression |
title_full | Extracellular PKM2 facilitates organ-tissue fibrosis progression |
title_fullStr | Extracellular PKM2 facilitates organ-tissue fibrosis progression |
title_full_unstemmed | Extracellular PKM2 facilitates organ-tissue fibrosis progression |
title_short | Extracellular PKM2 facilitates organ-tissue fibrosis progression |
title_sort | extracellular pkm2 facilitates organ-tissue fibrosis progression |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8517170/ https://www.ncbi.nlm.nih.gov/pubmed/34693222 http://dx.doi.org/10.1016/j.isci.2021.103165 |
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