Axl Inhibitor R428 Enhances TRAIL-Mediated Apoptosis Through Downregulation of c-FLIP and Survivin Expression in Renal Carcinoma
Identifieur interne : 000604 ( Pmc/Curation ); précédent : 000603; suivant : 000605Axl Inhibitor R428 Enhances TRAIL-Mediated Apoptosis Through Downregulation of c-FLIP and Survivin Expression in Renal Carcinoma
Auteurs : Seon Min Woo [Corée du Sud] ; Kyoung-Jin Min [Corée du Sud] ; Seung Un Seo [Corée du Sud] ; Shin Kim [Corée du Sud] ; Peter Kubatka [Slovaquie] ; Jong-Wook Park [Corée du Sud] ; Taeg Kyu Kwon [Corée du Sud]Source :
- International Journal of Molecular Sciences [ 1422-0067 ] ; 2019.
Abstract
R428, a selective small molecule Axl inhibitor, is known to have anti-cancer effects, such as inhibition of invasion and proliferation and induction of cell death in cancer cells. The Axl receptor tyrosine kinase is highly expressed in cancer cells and the level of Axl expression is associated with survival, metastasis, and drug resistance of many cancer cells. However, the effect of Axl inhibition on overcoming anti-cancer drugs resistance is unclear. Therefore, we investigated the capability of Axl inhibition as a therapeutic agent for the induction of TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) sensitivity. In this study, R428 markedly sensitized cancer cells to TRAIL-induced apoptotic cell death, but not in normal human skin fibroblast (HSF) and human umbilical vein cells (EA.hy926). Moreover, knockdown of Axl by siRNA also increased TRAIL-induced apoptosis. R428 decreased c-FLIP proteins levels via induction of miR-708 expression and survivin protein levels at the post-translational level, and we found that knockdown of Axl also decreased both c-FLIP and survivin protein expression. Overexpression of c-FLIP and survivin markedly inhibited R428 plus TRAIL-induced apoptosis. Furthermore, R428 sensitized cancer cells to multiple anti-cancer drugs-mediated cell death. Our results provide that inhibition of Axl could improve sensitivity to TRAIL through downregulation of c-FLIP and survivin expression in renal carcinoma cells. Taken together, Axl may be a tempting target to overcome TRAIL resistance.
Url:
DOI: 10.3390/ijms20133253
PubMed: 31269715
PubMed Central: 6651098
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Woo</name><affiliation wicri:level="1"><nlm:aff id="af1-ijms-20-03253">Department of Immunology, School of Medicine, Keimyung University, Daegu 42601, Korea</nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea>Department of Immunology, School of Medicine, Keimyung University, Daegu 42601</wicri:regionArea></affiliation></author><author><name sortKey="Min, Kyoung Jin" sort="Min, Kyoung Jin" uniqKey="Min K" first="Kyoung-Jin" last="Min">Kyoung-Jin Min</name><affiliation wicri:level="1"><nlm:aff id="af1-ijms-20-03253">Department of Immunology, School of Medicine, Keimyung University, Daegu 42601, Korea</nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea>Department of Immunology, School of Medicine, Keimyung University, Daegu 42601</wicri:regionArea></affiliation></author><author><name sortKey="Seo, Seung Un" sort="Seo, Seung Un" uniqKey="Seo S" first="Seung Un" last="Seo">Seung Un Seo</name><affiliation wicri:level="1"><nlm:aff id="af1-ijms-20-03253">Department of Immunology, School of Medicine, Keimyung University, Daegu 42601, Korea</nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea>Department of Immunology, School of Medicine, Keimyung University, Daegu 42601</wicri:regionArea></affiliation></author><author><name sortKey="Kim, Shin" sort="Kim, Shin" uniqKey="Kim S" first="Shin" last="Kim">Shin Kim</name><affiliation wicri:level="1"><nlm:aff id="af1-ijms-20-03253">Department of Immunology, School of Medicine, Keimyung University, Daegu 42601, Korea</nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea>Department of Immunology, School of Medicine, Keimyung University, Daegu 42601</wicri:regionArea></affiliation></author><author><name sortKey="Kubatka, Peter" sort="Kubatka, Peter" uniqKey="Kubatka P" first="Peter" last="Kubatka">Peter Kubatka</name><affiliation wicri:level="1"><nlm:aff id="af2-ijms-20-03253">Department of Medical Biology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 03601 Martin, Slovakia</nlm:aff><country xml:lang="fr">Slovaquie</country><wicri:regionArea>Department of Medical Biology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 03601 Martin</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="af3-ijms-20-03253">Department of Experimental Carcinogenesis, Division of Oncology, Biomedical Center Martin, Jessenius Faculty of Medicine, Comenius University in Bratislava, 03601 Martin, Slovakia</nlm:aff><country xml:lang="fr">Slovaquie</country><wicri:regionArea>Department of Experimental Carcinogenesis, Division of Oncology, Biomedical Center Martin, Jessenius Faculty of Medicine, Comenius University in Bratislava, 03601 Martin</wicri:regionArea></affiliation></author><author><name sortKey="Park, Jong Wook" sort="Park, Jong Wook" uniqKey="Park J" first="Jong-Wook" last="Park">Jong-Wook Park</name><affiliation wicri:level="1"><nlm:aff id="af1-ijms-20-03253">Department of Immunology, School of Medicine, Keimyung University, Daegu 42601, Korea</nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea>Department of Immunology, School of Medicine, Keimyung University, Daegu 42601</wicri:regionArea></affiliation></author><author><name sortKey="Kwon, Taeg Kyu" sort="Kwon, Taeg Kyu" uniqKey="Kwon T" first="Taeg Kyu" last="Kwon">Taeg Kyu Kwon</name><affiliation wicri:level="1"><nlm:aff id="af1-ijms-20-03253">Department of Immunology, School of Medicine, Keimyung University, Daegu 42601, Korea</nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea>Department of Immunology, School of Medicine, Keimyung University, Daegu 42601</wicri:regionArea></affiliation></author></analytic><series><title level="j">International Journal of Molecular Sciences</title><idno type="eISSN">1422-0067</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>R428, a selective small molecule Axl inhibitor, is known to have anti-cancer effects, such as inhibition of invasion and proliferation and induction of cell death in cancer cells. The Axl receptor tyrosine kinase is highly expressed in cancer cells and the level of Axl expression is associated with survival, metastasis, and drug resistance of many cancer cells. However, the effect of Axl inhibition on overcoming anti-cancer drugs resistance is unclear. Therefore, we investigated the capability of Axl inhibition as a therapeutic agent for the induction of TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) sensitivity. In this study, R428 markedly sensitized cancer cells to TRAIL-induced apoptotic cell death, but not in normal human skin fibroblast (HSF) and human umbilical vein cells (EA.hy926). Moreover, knockdown of Axl by siRNA also increased TRAIL-induced apoptosis. R428 decreased c-FLIP proteins levels via induction of miR-708 expression and survivin protein levels at the post-translational level, and we found that knockdown of Axl also decreased both c-FLIP and survivin protein expression. Overexpression of c-FLIP and survivin markedly inhibited R428 plus TRAIL-induced apoptosis. Furthermore, R428 sensitized cancer cells to multiple anti-cancer drugs-mediated cell death. Our results provide that inhibition of Axl could improve sensitivity to TRAIL through downregulation of c-FLIP and survivin expression in renal carcinoma cells. Taken together, Axl may be a tempting target to overcome TRAIL resistance.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Almasan, A" uniqKey="Almasan A">A. Almasan</name></author><author><name sortKey="Ashkenazi, A" uniqKey="Ashkenazi A">A. Ashkenazi</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Johnstone, R W" uniqKey="Johnstone R">R.W. Johnstone</name></author><author><name sortKey="Frew, A J" uniqKey="Frew A">A.J. Frew</name></author><author><name sortKey="Smyth, M J" uniqKey="Smyth M">M.J. 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Int J Mol Sci</journal-id><journal-id journal-id-type="iso-abbrev">Int J Mol Sci</journal-id><journal-id journal-id-type="publisher-id">ijms</journal-id><journal-title-group><journal-title>International Journal of Molecular Sciences</journal-title></journal-title-group><issn pub-type="epub">1422-0067</issn><publisher><publisher-name>MDPI</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">31269715</article-id><article-id pub-id-type="pmc">6651098</article-id><article-id pub-id-type="doi">10.3390/ijms20133253</article-id><article-id pub-id-type="publisher-id">ijms-20-03253</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Axl Inhibitor R428 Enhances TRAIL-Mediated Apoptosis Through Downregulation of c-FLIP and Survivin Expression in Renal Carcinoma</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Woo</surname><given-names>Seon Min</given-names></name><xref ref-type="aff" rid="af1-ijms-20-03253">1</xref></contrib><contrib contrib-type="author"><name><surname>Min</surname><given-names>Kyoung-jin</given-names></name><xref ref-type="aff" rid="af1-ijms-20-03253">1</xref></contrib><contrib contrib-type="author"><name><surname>Seo</surname><given-names>Seung Un</given-names></name><xref ref-type="aff" rid="af1-ijms-20-03253">1</xref></contrib><contrib contrib-type="author"><name><surname>Kim</surname><given-names>Shin</given-names></name><xref ref-type="aff" rid="af1-ijms-20-03253">1</xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0003-4312-5076</contrib-id><name><surname>Kubatka</surname><given-names>Peter</given-names></name><xref ref-type="aff" rid="af2-ijms-20-03253">2</xref><xref ref-type="aff" rid="af3-ijms-20-03253">3</xref></contrib><contrib contrib-type="author"><name><surname>Park</surname><given-names>Jong-Wook</given-names></name><xref ref-type="aff" rid="af1-ijms-20-03253">1</xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0003-1204-2059</contrib-id><name><surname>Kwon</surname><given-names>Taeg Kyu</given-names></name><xref ref-type="aff" rid="af1-ijms-20-03253">1</xref><xref rid="c1-ijms-20-03253" ref-type="corresp">*</xref></contrib></contrib-group><aff id="af1-ijms-20-03253"><label>1</label>Department of Immunology, School of Medicine, Keimyung University, Daegu 42601, Korea</aff><aff id="af2-ijms-20-03253"><label>2</label>Department of Medical Biology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 03601 Martin, Slovakia</aff><aff id="af3-ijms-20-03253"><label>3</label>Department of Experimental Carcinogenesis, Division of Oncology, Biomedical Center Martin, Jessenius Faculty of Medicine, Comenius University in Bratislava, 03601 Martin, Slovakia</aff><author-notes><corresp id="c1-ijms-20-03253"><label>*</label>Correspondence: <email>kwontk@dsmc.or.kr</email>; Tel.: +82-53-258-7358; Fax: +82-53-258-7355</corresp></author-notes><pub-date pub-type="epub"><day>02</day><month>7</month><year>2019</year></pub-date><pub-date pub-type="collection"><month>7</month><year>2019</year></pub-date><volume>20</volume><issue>13</issue><elocation-id>3253</elocation-id><history><date date-type="received"><day>11</day><month>6</month><year>2019</year></date><date date-type="accepted"><day>01</day><month>7</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>R428, a selective small molecule Axl inhibitor, is known to have anti-cancer effects, such as inhibition of invasion and proliferation and induction of cell death in cancer cells. The Axl receptor tyrosine kinase is highly expressed in cancer cells and the level of Axl expression is associated with survival, metastasis, and drug resistance of many cancer cells. However, the effect of Axl inhibition on overcoming anti-cancer drugs resistance is unclear. Therefore, we investigated the capability of Axl inhibition as a therapeutic agent for the induction of TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) sensitivity. In this study, R428 markedly sensitized cancer cells to TRAIL-induced apoptotic cell death, but not in normal human skin fibroblast (HSF) and human umbilical vein cells (EA.hy926). Moreover, knockdown of Axl by siRNA also increased TRAIL-induced apoptosis. R428 decreased c-FLIP proteins levels via induction of miR-708 expression and survivin protein levels at the post-translational level, and we found that knockdown of Axl also decreased both c-FLIP and survivin protein expression. Overexpression of c-FLIP and survivin markedly inhibited R428 plus TRAIL-induced apoptosis. Furthermore, R428 sensitized cancer cells to multiple anti-cancer drugs-mediated cell death. Our results provide that inhibition of Axl could improve sensitivity to TRAIL through downregulation of c-FLIP and survivin expression in renal carcinoma cells. Taken together, Axl may be a tempting target to overcome TRAIL resistance.</p></abstract><kwd-group><kwd>Axl</kwd><kwd>TRAIL</kwd><kwd>c-FLIP</kwd><kwd>survivin</kwd><kwd>apoptosis</kwd></kwd-group></article-meta></front><floats-group><fig id="ijms-20-03253-f001" orientation="portrait" position="float"><label>Figure 1</label><caption><p>Inhibition of Axl increases TRAIL (tumor necrosis factor-related apoptosis-inducing ligand)-mediated apoptosis of cancer cells, but not normal cells. (<bold>A</bold>) Caki cells were treated with Axl inhibitor (R428) for the indicated time kinetics. (<bold>B</bold>) Caki cells were treated with 1–10 µM R428 for 24 h (left panel). Caki cells were treated with R428 (3, 5 µM) in the presence or absence of TRAIL (30, 50 ng/mL) for 24 h (right panel). (<bold>C</bold>,<bold>D</bold>) Indicated cancer cells were treated with 5 µM R428 alone, 50 ng/mL TRAIL alone or R428 plus TRAIL for 24 h. (<bold>E</bold>) Caki, HSF and EA.hy926 cells were treated with 5 µM R428, 50 ng/mL TRAIL or R428 plus TRAIL for 24 h. The cell morphology was examined using interference light microscopy. The sub-G1 population and protein expression were detected by flow cytometry (<bold>B</bold>,<bold>C</bold>,<bold>E</bold>) and Western blotting (<bold>A</bold>,<bold>B</bold>,<bold>D</bold>), respectively. The band intensity was quantified using Image J (<bold>A</bold>,<bold>B</bold>,<bold>D</bold>). The values in graph (<bold>A</bold>–<bold>E</bold>) represent the mean ± SEM of three independent experiments. * <italic>p</italic> < 0.05 compared to the control. Black arrow (<bold>A</bold>) indicated specific band of p-Axl.</p></caption><graphic xlink:href="ijms-20-03253-g001"></graphic></fig><fig id="ijms-20-03253-f002" orientation="portrait" position="float"><label>Figure 2</label><caption><p>R428 increases caspase-dependent apoptosis through upregulation of DR5 expression and downregulation of c-FLIP and survivin expression. (<bold>A</bold>–<bold>D</bold>) Caki cells were treated with 5 µM R428 alone, 50 ng/mL TRAIL alone or R428 plus TRAIL for 24 h. DAPI staining (<bold>A</bold>), TUNEL staining (<bold>B</bold>), cytoplasmic histone-associated DNA fragments (<bold>C</bold>), and DEVDase (caspase-3) activity (<bold>D</bold>) were examined. Condensed chromatin rate determined by counting the number of apoptotic cells (<bold>A</bold>). (<bold>E</bold>) Caki cells were treated with 5 µM R428 plus 50 ng/mL TRAIL in the presence or absence of 20 µM z-VAD for 24 h. (<bold>F</bold>) Caki cells were treated with various concentrations of R428 for 24 h. (<bold>G</bold>,<bold>H</bold>) Caki cells were transfected with control (Con) or Axl siRNA for 24 h, and then cells were further incubated for 24 h (<bold>G</bold>) or were treated with 50 ng/mL TRAIL for 24 h (<bold>H</bold>). The sub-G1 population and protein expression were detected by flow cytometry (<bold>E</bold>,<bold>H</bold>) and Western blotting (<bold>E</bold>–<bold>H</bold>), respectively. The band intensity was quantified using Image J (<bold>E</bold>–<bold>H</bold>). The values in graph (<bold>A</bold>,<bold>C</bold>–<bold>H</bold>) represent the mean ± SEM of three independent experiments. * <italic>p</italic> < 0.01 compared to the control. # <italic>p</italic> < 0.01 compared to the R428 plus TRAIL. & <italic>p</italic> < 0.05 compared to the TRAIL in control siRNA.</p></caption><graphic xlink:href="ijms-20-03253-g002"></graphic></fig><fig id="ijms-20-03253-f003" orientation="portrait" position="float"><label>Figure 3</label><caption><p>Downregulation of c-FLIP is associated with induction of TRAIL-mediated apoptosis by R428. (<bold>A</bold>) Vector cells and c-FLIP-overexpressing cells (Caki/c-FLIP) were treated with 5 µM R428, 50 ng/mL TRAIL or R428 plus TRAIL 24 h. (<bold>B</bold>) Caki cells were treated with various concentrations of R428 for 24 h. The levels of mRNA were examined using RT-PCR. (<bold>C</bold>) Caki cells were treated with 5 µM in the presence or absence of 0.5 µM MG132 for 24 h. (<bold>D</bold>) Caki cells were treated with 5 µM R428 in the presence or absence of 20 µg/ml cycloheximide (CHX) for the indicated time kinetics. (<bold>E</bold>) Caki cells were treated with 5 µM R428 for 24 h, and then miR-708 expression was examined by qPCR. (<bold>F</bold>) For luciferase reporter assay, Caki cells transfected with c-FLIP 3′UTR wild-type (WT) and mutant (Mut), and cells were treated with 5 µM R428 for 24 h. The sub-G1 population and protein expression were detected by flow cytometry (<bold>A</bold>) and Western blotting (<bold>A</bold>,<bold>C</bold>,<bold>D</bold>), respectively. The band intensity was quantified using Image J (<bold>A</bold>,<bold>C</bold>,<bold>D</bold>). The values in graph (<bold>A</bold>,<bold>C</bold>–<bold>F</bold>) represent the mean ± SEM of three independent samples. * <italic>p</italic> < 0.01 compared to R428 plus TRAIL-treated Caki/Vec. ** <italic>p</italic> < 0.01 compared to control. # <italic>p</italic> < 0.05 compared to the R428-treated in c-FLIP 3′UTR WT.</p></caption><graphic xlink:href="ijms-20-03253-g003"></graphic></fig><fig id="ijms-20-03253-f004" orientation="portrait" position="float"><label>Figure 4</label><caption><p>Downregulation of survivin by R428 contributes to induction of TRAIL-mediated apoptosis. (<bold>A</bold>) Vector cells and survivin-overexpressing cells (Caki/Survivin) were treated with 5 µM R428, 50 ng/mL TRAIL or R428 plus TRAIL for 24 h. (<bold>B</bold>) Caki cells were treated with various concentrations of R428 for 24 h. The levels of mRNA were examined using RT-PCR. (<bold>C</bold>) Caki cells were treated with 5 µM R428 in the presence or absence of 20 µg/mL CHX for the indicated time kinetics. (<bold>D</bold>) Caki cells were treated with 5 µM in the presence or absence of 0.5 µM MG132 for 24 h. (<bold>E</bold>) The diagram showing the mechanism of R428-mediated TRAIL sensitization. The sub-G1 population and protein expression were detected by flow cytometry (<bold>A</bold>) and Western blotting (<bold>A</bold>,<bold>C</bold>,<bold>D</bold>), respectively. The band intensity was quantified using Image J (<bold>A</bold>,<bold>C</bold>,<bold>D</bold>). The values in graph (<bold>A</bold>,<bold>C</bold>,<bold>D</bold>) represent the mean ± SEM of three independent samples. * <italic>p</italic> < 0.01 compared to R428 plus TRAIL-treated Caki/Vec. ** <italic>p</italic> < 0.01 compared to the control. # <italic>p</italic> < 0.01 compared to the R428.</p></caption><graphic xlink:href="ijms-20-03253-g004"></graphic></fig></floats-group></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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