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Oxygen tension regulates lysosomal activation and receptor tyrosine kinase degradation

View ORCID ProfileJaewoo Hong, Todd R. Wuest, Yongfen Min, P. Charles Lin
doi: https://doi.org/10.1101/727495
Jaewoo Hong
Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland, 21702, United States of America
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  • ORCID record for Jaewoo Hong
Todd R. Wuest
Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland, 21702, United States of America
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Yongfen Min
Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland, 21702, United States of America
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P. Charles Lin
Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland, 21702, United States of America
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  • For correspondence: p.lin@nih.gov
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Abstract

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 mammalian tissue culture 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.

One Sentence Summary Hypoxia suppresses lysosomal activation and proteolysis.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. This article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available for use under a CC0 license.
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Posted August 06, 2019.
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Oxygen tension regulates lysosomal activation and receptor tyrosine kinase degradation
Jaewoo Hong, Todd R. Wuest, Yongfen Min, P. Charles Lin
bioRxiv 727495; doi: https://doi.org/10.1101/727495
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Oxygen tension regulates lysosomal activation and receptor tyrosine kinase degradation
Jaewoo Hong, Todd R. Wuest, Yongfen Min, P. Charles Lin
bioRxiv 727495; doi: https://doi.org/10.1101/727495

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