Oxygen Tension Regulates Lysosomal Activation and Receptor Tyrosine Kinase Degradation
Identifieur interne : 000B96 ( Ncbi/Checkpoint ); précédent : 000B95; suivant : 000B97Oxygen Tension Regulates Lysosomal Activation and Receptor Tyrosine Kinase Degradation
Auteurs : Jaewoo Hong ; Todd R. Wuest ; Yongfen Min ; P. Charles LinSource :
- Cancers [ 2072-6694 ] ; 2019.
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 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.
Url:
DOI: 10.3390/cancers11111653
PubMed: 31717697
PubMed Central: 6896048
Affiliations:
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<author><name sortKey="Wuest, Todd R" sort="Wuest, Todd R" uniqKey="Wuest T" first="Todd R." last="Wuest">Todd R. Wuest</name>
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<author><name sortKey="Min, Yongfen" sort="Min, Yongfen" uniqKey="Min Y" first="Yongfen" last="Min">Yongfen Min</name>
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<author><name sortKey="Lin, P Charles" sort="Lin, P Charles" uniqKey="Lin P" first="P. Charles" last="Lin">P. Charles Lin</name>
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<front><div type="abstract" xml:lang="en"><p>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.</p>
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