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Oxygen Tension Regulates Lysosomal Activation and Receptor Tyrosine Kinase Degradation
Oxygen sensing is crucial for adaptation to variable habitats and physiological conditions. Low oxygen tension, or hypoxia, is a common feature of solid tumors, and hypoxic tumors are often more aggressive and resistant to therapy. Here we show that, in cultured mammalian cells, hypoxia suppressed l...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6896048/ https://www.ncbi.nlm.nih.gov/pubmed/31717697 http://dx.doi.org/10.3390/cancers11111653 |
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author | Hong, Jaewoo Wuest, Todd R. Min, Yongfen Lin, P. Charles |
author_facet | Hong, Jaewoo Wuest, Todd R. Min, Yongfen Lin, P. Charles |
author_sort | Hong, Jaewoo |
collection | PubMed |
description | Oxygen sensing is crucial for adaptation to variable habitats and physiological conditions. Low oxygen tension, or hypoxia, is a common feature of solid tumors, and hypoxic tumors are often more aggressive and resistant to therapy. Here we show that, in cultured mammalian cells, hypoxia suppressed lysosomal acidification/activation and receptor tyrosine kinase (RTK) degradation. Hypoxia down-regulated mTORc1, reducing its ability to activate transcription factor EB (TFEB), a master regulator of V-ATPase, the lysosomal proton pump. Hypoxia prevented epidermal growth factor receptor (EGFR) degradation in tumor tissues, whereas activation of lysosomes enhanced tumor cell response to anti-EGFR treatment. Our results link oxygen tension and lysosomal activity, provide a molecular explanation of the malignant phenotype associated with hypoxic tumors, and suggest activation of lysosomes may provide therapeutic benefit in RTK-targeted cancer therapy. |
format | Online Article Text |
id | pubmed-6896048 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-68960482019-12-23 Oxygen Tension Regulates Lysosomal Activation and Receptor Tyrosine Kinase Degradation Hong, Jaewoo Wuest, Todd R. Min, Yongfen Lin, P. Charles Cancers (Basel) Article Oxygen sensing is crucial for adaptation to variable habitats and physiological conditions. Low oxygen tension, or hypoxia, is a common feature of solid tumors, and hypoxic tumors are often more aggressive and resistant to therapy. Here we show that, in cultured mammalian cells, hypoxia suppressed lysosomal acidification/activation and receptor tyrosine kinase (RTK) degradation. Hypoxia down-regulated mTORc1, reducing its ability to activate transcription factor EB (TFEB), a master regulator of V-ATPase, the lysosomal proton pump. Hypoxia prevented epidermal growth factor receptor (EGFR) degradation in tumor tissues, whereas activation of lysosomes enhanced tumor cell response to anti-EGFR treatment. Our results link oxygen tension and lysosomal activity, provide a molecular explanation of the malignant phenotype associated with hypoxic tumors, and suggest activation of lysosomes may provide therapeutic benefit in RTK-targeted cancer therapy. MDPI 2019-10-25 /pmc/articles/PMC6896048/ /pubmed/31717697 http://dx.doi.org/10.3390/cancers11111653 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Hong, Jaewoo Wuest, Todd R. Min, Yongfen Lin, P. Charles Oxygen Tension Regulates Lysosomal Activation and Receptor Tyrosine Kinase Degradation |
title | Oxygen Tension Regulates Lysosomal Activation and Receptor Tyrosine Kinase Degradation |
title_full | Oxygen Tension Regulates Lysosomal Activation and Receptor Tyrosine Kinase Degradation |
title_fullStr | Oxygen Tension Regulates Lysosomal Activation and Receptor Tyrosine Kinase Degradation |
title_full_unstemmed | Oxygen Tension Regulates Lysosomal Activation and Receptor Tyrosine Kinase Degradation |
title_short | Oxygen Tension Regulates Lysosomal Activation and Receptor Tyrosine Kinase Degradation |
title_sort | oxygen tension regulates lysosomal activation and receptor tyrosine kinase degradation |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6896048/ https://www.ncbi.nlm.nih.gov/pubmed/31717697 http://dx.doi.org/10.3390/cancers11111653 |
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