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Matrix rigidity regulates a switch between TGF-β1–induced apoptosis and epithelial–mesenchymal transition

The transforming growth factor-β (TGF-β) signaling pathway is often misregulated during cancer progression. In early stages of tumorigenesis, TGF-β acts as a tumor suppressor by inhibiting proliferation and inducing apoptosis. However, as the disease progresses, TGF-β switches to promote tumorigenic...

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Autores principales: Leight, Jennifer L., Wozniak, Michele A., Chen, Sophia, Lynch, Michelle L., Chen, Christopher S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The American Society for Cell Biology 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3290638/
https://www.ncbi.nlm.nih.gov/pubmed/22238361
http://dx.doi.org/10.1091/mbc.E11-06-0537
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author Leight, Jennifer L.
Wozniak, Michele A.
Chen, Sophia
Lynch, Michelle L.
Chen, Christopher S.
author_facet Leight, Jennifer L.
Wozniak, Michele A.
Chen, Sophia
Lynch, Michelle L.
Chen, Christopher S.
author_sort Leight, Jennifer L.
collection PubMed
description The transforming growth factor-β (TGF-β) signaling pathway is often misregulated during cancer progression. In early stages of tumorigenesis, TGF-β acts as a tumor suppressor by inhibiting proliferation and inducing apoptosis. However, as the disease progresses, TGF-β switches to promote tumorigenic cell functions, such as epithelial–mesenchymal transition (EMT) and increased cell motility. Dramatic changes in the cellular microenvironment are also correlated with tumor progression, including an increase in tissue stiffness. However, it is unknown whether these changes in tissue stiffness can regulate the effects of TGF-β. To this end, we examined normal murine mammary gland cells and Madin–Darby canine kidney epithelial cells cultured on polyacrylamide gels with varying rigidity and treated with TGF-β1. Varying matrix rigidity switched the functional response to TGF-β1. Decreasing rigidity increased TGF-β1–induced apoptosis, whereas increasing rigidity resulted in EMT. Matrix rigidity did not change Smad signaling, but instead regulated the PI3K/Akt signaling pathway. Direct genetic and pharmacologic manipulations further demonstrated a role for PI3K/Akt signaling in the apoptotic and EMT responses. These findings demonstrate that matrix rigidity regulates a previously undescribed switch in TGF-β–induced cell functions and provide insight into how changes in tissue mechanics during disease might contribute to the cellular response to TGF-β.
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spelling pubmed-32906382012-05-16 Matrix rigidity regulates a switch between TGF-β1–induced apoptosis and epithelial–mesenchymal transition Leight, Jennifer L. Wozniak, Michele A. Chen, Sophia Lynch, Michelle L. Chen, Christopher S. Mol Biol Cell Articles The transforming growth factor-β (TGF-β) signaling pathway is often misregulated during cancer progression. In early stages of tumorigenesis, TGF-β acts as a tumor suppressor by inhibiting proliferation and inducing apoptosis. However, as the disease progresses, TGF-β switches to promote tumorigenic cell functions, such as epithelial–mesenchymal transition (EMT) and increased cell motility. Dramatic changes in the cellular microenvironment are also correlated with tumor progression, including an increase in tissue stiffness. However, it is unknown whether these changes in tissue stiffness can regulate the effects of TGF-β. To this end, we examined normal murine mammary gland cells and Madin–Darby canine kidney epithelial cells cultured on polyacrylamide gels with varying rigidity and treated with TGF-β1. Varying matrix rigidity switched the functional response to TGF-β1. Decreasing rigidity increased TGF-β1–induced apoptosis, whereas increasing rigidity resulted in EMT. Matrix rigidity did not change Smad signaling, but instead regulated the PI3K/Akt signaling pathway. Direct genetic and pharmacologic manipulations further demonstrated a role for PI3K/Akt signaling in the apoptotic and EMT responses. These findings demonstrate that matrix rigidity regulates a previously undescribed switch in TGF-β–induced cell functions and provide insight into how changes in tissue mechanics during disease might contribute to the cellular response to TGF-β. The American Society for Cell Biology 2012-03-01 /pmc/articles/PMC3290638/ /pubmed/22238361 http://dx.doi.org/10.1091/mbc.E11-06-0537 Text en © 2012 Leight et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0). “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society of Cell Biology.
spellingShingle Articles
Leight, Jennifer L.
Wozniak, Michele A.
Chen, Sophia
Lynch, Michelle L.
Chen, Christopher S.
Matrix rigidity regulates a switch between TGF-β1–induced apoptosis and epithelial–mesenchymal transition
title Matrix rigidity regulates a switch between TGF-β1–induced apoptosis and epithelial–mesenchymal transition
title_full Matrix rigidity regulates a switch between TGF-β1–induced apoptosis and epithelial–mesenchymal transition
title_fullStr Matrix rigidity regulates a switch between TGF-β1–induced apoptosis and epithelial–mesenchymal transition
title_full_unstemmed Matrix rigidity regulates a switch between TGF-β1–induced apoptosis and epithelial–mesenchymal transition
title_short Matrix rigidity regulates a switch between TGF-β1–induced apoptosis and epithelial–mesenchymal transition
title_sort matrix rigidity regulates a switch between tgf-β1–induced apoptosis and epithelial–mesenchymal transition
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3290638/
https://www.ncbi.nlm.nih.gov/pubmed/22238361
http://dx.doi.org/10.1091/mbc.E11-06-0537
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