Oxygen Tension Regulates Lysosomal Activation and Receptor Tyrosine Kinase Degradation
Identifieur interne : 000512 ( Pmc/Checkpoint ); précédent : 000511; suivant : 000513Oxygen 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
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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></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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<front><journal-meta><journal-id journal-id-type="nlm-ta">Cancers (Basel)</journal-id><journal-id journal-id-type="iso-abbrev">Cancers (Basel)</journal-id><journal-id journal-id-type="publisher-id">cancers</journal-id><journal-title-group><journal-title>Cancers</journal-title></journal-title-group><issn pub-type="epub">2072-6694</issn><publisher><publisher-name>MDPI</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">31717697</article-id><article-id pub-id-type="pmc">6896048</article-id><article-id pub-id-type="doi">10.3390/cancers11111653</article-id><article-id pub-id-type="publisher-id">cancers-11-01653</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Oxygen Tension Regulates Lysosomal Activation and Receptor Tyrosine Kinase Degradation</article-title></title-group><contrib-group><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0003-3456-3672</contrib-id><name><surname>Hong</surname><given-names>Jaewoo</given-names></name><xref rid="c1-cancers-11-01653" ref-type="corresp">*</xref></contrib><contrib contrib-type="author"><name><surname>Wuest</surname><given-names>Todd R.</given-names></name></contrib><contrib contrib-type="author"><name><surname>Min</surname><given-names>Yongfen</given-names></name></contrib><contrib contrib-type="author"><name><surname>Lin</surname><given-names>P. Charles</given-names></name><xref rid="c1-cancers-11-01653" ref-type="corresp">*</xref></contrib></contrib-group><aff id="af1-cancers-11-01653">Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA;<email>toddwuest1@gmail.com</email> (T.R.W.);<email>yongfen.min@nih.gov</email> (Y.M.)</aff><author-notes><corresp id="c1-cancers-11-01653"><label>*</label>Correspondence: <email>jaewoo.hong@nih.gov</email> (J.H.); <email>p.lin@nih.gov</email> (P.C.L.)</corresp></author-notes><pub-date pub-type="epub"><day>25</day><month>10</month><year>2019</year></pub-date><pub-date pub-type="collection"><month>11</month><year>2019</year></pub-date><volume>11</volume><issue>11</issue><elocation-id>1653</elocation-id><history><date date-type="received"><day>27</day><month>9</month><year>2019</year></date><date date-type="accepted"><day>22</day><month>10</month><year>2019</year></date></history><permissions><copyright-statement>© 2019 by the authors.</copyright-statement><copyright-year>2019</copyright-year><license license-type="open-access"><license-p>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 (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link>).</license-p></license></permissions><abstract><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></abstract><kwd-group><kwd>hypoxia</kwd><kwd>lysosome</kwd><kwd>oxygen tension</kwd><kwd>receptor tyrosine kinase</kwd><kwd>EGFR</kwd></kwd-group></article-meta></front><floats-group><fig id="cancers-11-01653-f001" orientation="portrait" position="float"><label>Figure 1</label><caption><p>Hypoxia inhibits lysosomal activity via suppression of V-ATPase expression. HUVECs, HeLa and A549 were serum-starved overnight, followed by stimulation with 50 ng/mL of epidermal growth factor (EGF) under 20% or 1% oxygen conditions for 5 h. Cell lysates were used to measure epidermal growth factor receptor (EGFR) levels by Western blot (<bold>A</bold>). Serum starved cells were treated with 50 ng/mL of EGF in the presence or absence of 100 nM of Bafilomycin A1 for 5 h, followed by Western blot for EGFR (<bold>B</bold>). HUVECs were incubated in either 20% or 1% O<sub>2</sub> in the presence of LysoBrite-NIR for 4 h. Cells were fixed and immunostained for Lamp2 (<bold>C</bold>). Images were collected from confocal microscopy. Representative images are shown. HUVECs were cultured in 1% O<sub>2</sub> for the indicated times, followed by Western blot (<bold>D</bold>). HUVECs were infected with ATP6V1B2 shRNA lentiviral or control vectors (<bold>E</bold>), or infected with lentiviral vectors for ATP6V1A and/or ATP6V1B2, for 2 days (<bold>F</bold>). The cells were serum-starved overnight followed by stimulation with 50 ng/mL of EGF for 5 h. <xref ref-type="app" rid="app1-cancers-11-01653">Figure S5</xref> shows the raw data for Western blots of <xref ref-type="fig" rid="cancers-11-01653-f001">Figure 1</xref>.</p></caption><graphic xlink:href="cancers-11-01653-g001"></graphic></fig><fig id="cancers-11-01653-f002" orientation="portrait" position="float"><label>Figure 2</label><caption><p>Hypoxia suppresses lysosomal acidification through mTORc1. HUVECs were incubated in 1% O<sub>2</sub> for the indicated times, and phospho- and total mTOR levels were detected from cell lysates (<bold>A</bold>). HUVECs were treated with 10 or 50 nM of rapamycin overnight. Cell lysates were subjected to Western blot (<bold>B</bold>). Lung endothelial cells were isolated from <italic>RHEB</italic>- or <italic>RICTOR</italic>-floxed mice followed by infection with GFP or Cre expressing adenoviral vectors for 24 h, followed by Western blot (<bold>C</bold>). HUVECs were incubated in the presence of LysoBrite-NIR in the presence or absence of 10 nM of rapamycin or AZD2014 to block mTORc1(<bold>D</bold>), or in the presence or absence of 2 μM of MHY1485 to activate mTORc1(<bold>E</bold>), overnight. Wheat germ agglutinin (WGA) was used for counter staining. Images were collected from confocal microscopy. Representative images are shown. <xref ref-type="app" rid="app1-cancers-11-01653">Figure S6</xref> shows the raw data for Western blots of <xref ref-type="fig" rid="cancers-11-01653-f002">Figure 2</xref>.</p></caption><graphic xlink:href="cancers-11-01653-g002"></graphic></fig><fig id="cancers-11-01653-f003" orientation="portrait" position="float"><label>Figure 3</label><caption><p>mTORc1 phosphorylates TFEB at S463. HeLa cells transfected with Myc tagged wild-type (WT) or TFEB mutant constructs were incubated in either 20% or 1% O<sub>2</sub> for 24 h, followed by immunostaining using Myc antibody (<bold>A</bold>). HeLa cells transfected with TFEB-Myc expression vectors for 1 day, followed by stimulation with vehicle control, 2 μM of MHY1485, or 10 nM of AZD2014 for 30 min. TFEB was immunoprecipitated with antibodies against the Myc tag, followed by mass-spectrometry analysis (<bold>B</bold>). HeLa cells transfected with S462D or S463D mutants were stimulated with vehicle or 10 nM of AZD2014 for 30 min, followed by immunostaining for TFEB (<bold>C</bold>). HeLa cells transfected with S463A or S463D mutants were incubated in 20% or 1% O<sub>2</sub> for 4 h, followed by immunostaining for TFEB (<bold>D</bold>). Images were collected from confocal microscopy. Representative images are shown.</p></caption><graphic xlink:href="cancers-11-01653-g003"></graphic></fig><fig id="cancers-11-01653-f004" orientation="portrait" position="float"><label>Figure 4</label><caption><p>Activation of lysosomes enhances tumor cell response to anti-EGFR inhibition. Cryosectioned murine B16 melanoma tissues were stained with antibodies against EGFR and HIF-1α and imaged with confocal microscopy (<bold>A</bold>). Paraffin sections of human colon and stomach cancer tissues were stained against EGFR and HIF-1α (<bold>B</bold>) and p-ERK and HIF-1α (<bold>C</bold>) and imaged with confocal microscopy. Representative images are shown. HUVEC, A549, HeLa, and DLD-1 were incubated in 20% or 1% O<sub>2</sub> for 5 h. The mRNA levels of EGFR and VEGF were measured by qPCR (<bold>D</bold>). * <italic>p</italic> < 0.05, ** <italic>p</italic> < 0.01. Human tumor cells transfected with WT TFEB, or S463A and S463D mutant expression vectors were treated with control IgG or anti-EGFR antibodies at 10 μg/mL overnight. Cell proliferation was measured by the XTT assay (<bold>E</bold>). * <italic>p</italic> < 0.05, ** <italic>p</italic> < 0.01, *** <italic>p</italic> < 0.001. The experiment was done in triplicates and repeated twice.</p></caption><graphic xlink:href="cancers-11-01653-g004"></graphic></fig></floats-group></pmc><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. 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