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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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Oxygen Tension Regulates Lysosomal Activation and Receptor Tyrosine Kinase Degradation</title><author><name sortKey="Hong, Jaewoo" sort="Hong, Jaewoo" uniqKey="Hong J" first="Jaewoo" last="Hong">Jaewoo Hong</name></author><author><name sortKey="Wuest, Todd R" sort="Wuest, Todd R" uniqKey="Wuest T" first="Todd R." last="Wuest">Todd R. Wuest</name></author><author><name sortKey="Min, Yongfen" sort="Min, Yongfen" uniqKey="Min Y" first="Yongfen" last="Min">Yongfen Min</name></author><author><name sortKey="Lin, P Charles" sort="Lin, P Charles" uniqKey="Lin P" first="P. Charles" last="Lin">P. Charles Lin</name></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">31717697</idno><idno type="pmc">6896048</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6896048</idno><idno type="RBID">PMC:6896048</idno><idno type="doi">10.3390/cancers11111653</idno><date when="2019">2019</date><idno type="wicri:Area/Pmc/Corpus">000461</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000461</idno><idno type="wicri:Area/Pmc/Curation">000461</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000461</idno><idno type="wicri:Area/Pmc/Checkpoint">000512</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Checkpoint">000512</idno><idno type="wicri:Area/Ncbi/Merge">000B96</idno><idno type="wicri:Area/Ncbi/Curation">000B96</idno><idno type="wicri:Area/Ncbi/Checkpoint">000B96</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Oxygen Tension Regulates Lysosomal Activation and Receptor Tyrosine Kinase Degradation</title><author><name sortKey="Hong, Jaewoo" sort="Hong, Jaewoo" uniqKey="Hong J" first="Jaewoo" last="Hong">Jaewoo Hong</name></author><author><name sortKey="Wuest, Todd R" sort="Wuest, Todd R" uniqKey="Wuest T" first="Todd R." last="Wuest">Todd R. Wuest</name></author><author><name sortKey="Min, Yongfen" sort="Min, Yongfen" uniqKey="Min Y" first="Yongfen" last="Min">Yongfen Min</name></author><author><name sortKey="Lin, P Charles" sort="Lin, P Charles" uniqKey="Lin P" first="P. Charles" last="Lin">P. Charles Lin</name></author></analytic><series><title level="j">Cancers</title><idno type="eISSN">2072-6694</idno><imprint><date when="2019">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><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></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Semenza, G L" uniqKey="Semenza G">G.L. Semenza</name></author><author><name sortKey="Agani, F" uniqKey="Agani F">F. Agani</name></author><author><name sortKey="Feldser, D" uniqKey="Feldser D">D. Feldser</name></author><author><name sortKey="Iyer, N" uniqKey="Iyer N">N. 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Baselga</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Vaupel, P" uniqKey="Vaupel P">P. Vaupel</name></author><author><name sortKey="Mayer, A" uniqKey="Mayer A">A. Mayer</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Debusk, L M" uniqKey="Debusk L">L.M. DeBusk</name></author><author><name sortKey="Boelte, K" uniqKey="Boelte K">K. Boelte</name></author><author><name sortKey="Min, Y" uniqKey="Min Y">Y. Min</name></author><author><name sortKey="Lin, P C" uniqKey="Lin P">P.C. Lin</name></author></analytic></biblStruct></listBibl></div1></back></TEI><affiliations><list></list><tree><noCountry><name sortKey="Hong, Jaewoo" sort="Hong, Jaewoo" uniqKey="Hong J" first="Jaewoo" last="Hong">Jaewoo Hong</name><name sortKey="Lin, P Charles" sort="Lin, P Charles" uniqKey="Lin P" first="P. Charles" last="Lin">P. Charles Lin</name><name sortKey="Min, Yongfen" sort="Min, Yongfen" uniqKey="Min Y" first="Yongfen" last="Min">Yongfen Min</name><name sortKey="Wuest, Todd R" sort="Wuest, Todd R" uniqKey="Wuest T" first="Todd R." last="Wuest">Todd R. Wuest</name></noCountry></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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