Naja atra Cardiotoxin 3 Elicits Autophagy and Apoptosis in U937 Human Leukemia Cells through the Ca2+/PP2A/AMPK Axis
Identifieur interne : 000A43 ( Ncbi/Merge ); précédent : 000A42; suivant : 000A44Naja atra Cardiotoxin 3 Elicits Autophagy and Apoptosis in U937 Human Leukemia Cells through the Ca2+/PP2A/AMPK Axis
Auteurs : Jing-Ting Chiou [Taïwan] ; Yi-Jun Shi [Taïwan] ; Liang-Jun Wang [Taïwan] ; Chia-Hui Huang [Taïwan] ; Yuan-Chin Lee [Taïwan] ; Long-Sen Chang [Taïwan]Source :
- Toxins [ 2072-6651 ] ; 2019.
Abstract
Cardiotoxins (CTXs) are suggested to exert their cytotoxicity through cell membrane damage. Other studies show that penetration of CTXs into cells elicits mitochondrial fragmentation or lysosome disruption, leading to cell death. Considering the role of AMPK-activated protein kinase (AMPK) in mitochondrial biogenesis and lysosomal biogenesis, we aimed to investigate whether the AMPK-mediated pathway modulated
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DOI: 10.3390/toxins11090527
PubMed: 31547294
PubMed Central: 6784133
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en"><italic>Naja atra</italic> Cardiotoxin 3 Elicits Autophagy and Apoptosis in U937 Human Leukemia Cells through the Ca<sup>2+</sup>/PP2A/AMPK Axis</title><author><name sortKey="Chiou, Jing Ting" sort="Chiou, Jing Ting" uniqKey="Chiou J" first="Jing-Ting" last="Chiou">Jing-Ting Chiou</name><affiliation wicri:level="1"><nlm:aff id="af1-toxins-11-00527">Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan</nlm:aff><country xml:lang="fr">Taïwan</country><wicri:regionArea>Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804</wicri:regionArea><wicri:noRegion>Kaohsiung 804</wicri:noRegion></affiliation></author><author><name sortKey="Shi, Yi Jun" sort="Shi, Yi Jun" uniqKey="Shi Y" first="Yi-Jun" last="Shi">Yi-Jun Shi</name><affiliation wicri:level="1"><nlm:aff id="af1-toxins-11-00527">Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan</nlm:aff><country xml:lang="fr">Taïwan</country><wicri:regionArea>Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804</wicri:regionArea><wicri:noRegion>Kaohsiung 804</wicri:noRegion></affiliation></author><author><name sortKey="Wang, Liang Jun" sort="Wang, Liang Jun" uniqKey="Wang L" first="Liang-Jun" last="Wang">Liang-Jun Wang</name><affiliation wicri:level="1"><nlm:aff id="af1-toxins-11-00527">Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan</nlm:aff><country xml:lang="fr">Taïwan</country><wicri:regionArea>Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804</wicri:regionArea><wicri:noRegion>Kaohsiung 804</wicri:noRegion></affiliation></author><author><name sortKey="Huang, Chia Hui" sort="Huang, Chia Hui" uniqKey="Huang C" first="Chia-Hui" last="Huang">Chia-Hui Huang</name><affiliation wicri:level="1"><nlm:aff id="af1-toxins-11-00527">Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan</nlm:aff><country xml:lang="fr">Taïwan</country><wicri:regionArea>Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804</wicri:regionArea><wicri:noRegion>Kaohsiung 804</wicri:noRegion></affiliation></author><author><name sortKey="Lee, Yuan Chin" sort="Lee, Yuan Chin" uniqKey="Lee Y" first="Yuan-Chin" last="Lee">Yuan-Chin Lee</name><affiliation wicri:level="1"><nlm:aff id="af1-toxins-11-00527">Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan</nlm:aff><country xml:lang="fr">Taïwan</country><wicri:regionArea>Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804</wicri:regionArea><wicri:noRegion>Kaohsiung 804</wicri:noRegion></affiliation></author><author><name sortKey="Chang, Long Sen" sort="Chang, Long Sen" uniqKey="Chang L" first="Long-Sen" last="Chang">Long-Sen Chang</name><affiliation wicri:level="1"><nlm:aff id="af1-toxins-11-00527">Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan</nlm:aff><country xml:lang="fr">Taïwan</country><wicri:regionArea>Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804</wicri:regionArea><wicri:noRegion>Kaohsiung 804</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="af2-toxins-11-00527">Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 807, Taiwan</nlm:aff><country xml:lang="fr">Taïwan</country><wicri:regionArea>Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 807</wicri:regionArea><wicri:noRegion>Kaohsiung 807</wicri:noRegion></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">31547294</idno><idno type="pmc">6784133</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6784133</idno><idno type="RBID">PMC:6784133</idno><idno type="doi">10.3390/toxins11090527</idno><date when="2019">2019</date><idno type="wicri:Area/Pmc/Corpus">000834</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000834</idno><idno type="wicri:Area/Pmc/Curation">000834</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000834</idno><idno type="wicri:Area/Pmc/Checkpoint">000A81</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Checkpoint">000A81</idno><idno type="wicri:Area/Ncbi/Merge">000A43</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main"><italic>Naja atra</italic> Cardiotoxin 3 Elicits Autophagy and Apoptosis in U937 Human Leukemia Cells through the Ca<sup>2+</sup>/PP2A/AMPK Axis</title><author><name sortKey="Chiou, Jing Ting" sort="Chiou, Jing Ting" uniqKey="Chiou J" first="Jing-Ting" last="Chiou">Jing-Ting Chiou</name><affiliation wicri:level="1"><nlm:aff id="af1-toxins-11-00527">Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan</nlm:aff><country xml:lang="fr">Taïwan</country><wicri:regionArea>Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804</wicri:regionArea><wicri:noRegion>Kaohsiung 804</wicri:noRegion></affiliation></author><author><name sortKey="Shi, Yi Jun" sort="Shi, Yi Jun" uniqKey="Shi Y" first="Yi-Jun" last="Shi">Yi-Jun Shi</name><affiliation wicri:level="1"><nlm:aff id="af1-toxins-11-00527">Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan</nlm:aff><country xml:lang="fr">Taïwan</country><wicri:regionArea>Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804</wicri:regionArea><wicri:noRegion>Kaohsiung 804</wicri:noRegion></affiliation></author><author><name sortKey="Wang, Liang Jun" sort="Wang, Liang Jun" uniqKey="Wang L" first="Liang-Jun" last="Wang">Liang-Jun Wang</name><affiliation wicri:level="1"><nlm:aff id="af1-toxins-11-00527">Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan</nlm:aff><country xml:lang="fr">Taïwan</country><wicri:regionArea>Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804</wicri:regionArea><wicri:noRegion>Kaohsiung 804</wicri:noRegion></affiliation></author><author><name sortKey="Huang, Chia Hui" sort="Huang, Chia Hui" uniqKey="Huang C" first="Chia-Hui" last="Huang">Chia-Hui Huang</name><affiliation wicri:level="1"><nlm:aff id="af1-toxins-11-00527">Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan</nlm:aff><country xml:lang="fr">Taïwan</country><wicri:regionArea>Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804</wicri:regionArea><wicri:noRegion>Kaohsiung 804</wicri:noRegion></affiliation></author><author><name sortKey="Lee, Yuan Chin" sort="Lee, Yuan Chin" uniqKey="Lee Y" first="Yuan-Chin" last="Lee">Yuan-Chin Lee</name><affiliation wicri:level="1"><nlm:aff id="af1-toxins-11-00527">Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan</nlm:aff><country xml:lang="fr">Taïwan</country><wicri:regionArea>Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804</wicri:regionArea><wicri:noRegion>Kaohsiung 804</wicri:noRegion></affiliation></author><author><name sortKey="Chang, Long Sen" sort="Chang, Long Sen" uniqKey="Chang L" first="Long-Sen" last="Chang">Long-Sen Chang</name><affiliation wicri:level="1"><nlm:aff id="af1-toxins-11-00527">Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan</nlm:aff><country xml:lang="fr">Taïwan</country><wicri:regionArea>Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804</wicri:regionArea><wicri:noRegion>Kaohsiung 804</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="af2-toxins-11-00527">Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 807, Taiwan</nlm:aff><country xml:lang="fr">Taïwan</country><wicri:regionArea>Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 807</wicri:regionArea><wicri:noRegion>Kaohsiung 807</wicri:noRegion></affiliation></author></analytic><series><title level="j">Toxins</title><idno type="eISSN">2072-6651</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>Cardiotoxins (CTXs) are suggested to exert their cytotoxicity through cell membrane damage. Other studies show that penetration of CTXs into cells elicits mitochondrial fragmentation or lysosome disruption, leading to cell death. Considering the role of AMPK-activated protein kinase (AMPK) in mitochondrial biogenesis and lysosomal biogenesis, we aimed to investigate whether the AMPK-mediated pathway modulated <italic>Naja atra</italic> (Taiwan cobra) CTX3 cytotoxicity in U937 human leukemia cells. Our results showed that CTX3 induced autophagy and apoptosis in U937 cells, whereas autophagic inhibitors suppressed CTX3-induced apoptosis. CTX3 treatment elicited Ca<sup>2+</sup>-dependent degradation of the protein phosphatase 2A (PP2A) catalytic subunit (PP2Acα) and phosphorylation of AMPKα. Overexpression of PP2Acα mitigated the CTX3-induced AMPKα phosphorylation. CTX3-induced autophagy was via AMPK-mediated suppression of the Akt/mTOR pathway. Removal of Ca<sup>2+</sup> or suppression of AMPKα phosphorylation inhibited the CTX3-induced cell death. CTX3 was unable to induce autophagy and apoptosis in U937 cells expressing constitutively active Akt. Met-modified CTX3 retained its membrane-perturbing activity, however, it did not induce AMPK activation and death of U937 cells. These results conclusively indicate that CTX3 induces autophagy and apoptosis in U937 cells via the Ca<sup>2+</sup>/PP2A/AMPK axis, and suggest that the membrane-perturbing activity of CTX3 is not crucial for the cell death signaling pathway induction.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Dufton, M J" uniqKey="Dufton M">M.J. Dufton</name></author><author><name sortKey="Hider, R C" uniqKey="Hider R">R.C. Hider</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Konshina, A G" uniqKey="Konshina A">A.G. Konshina</name></author><author><name sortKey="Dubovskii, P V" uniqKey="Dubovskii P">P.V. 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Toxins (Basel)</journal-id><journal-id journal-id-type="iso-abbrev">Toxins (Basel)</journal-id><journal-id journal-id-type="publisher-id">toxins</journal-id><journal-title-group><journal-title>Toxins</journal-title></journal-title-group><issn pub-type="epub">2072-6651</issn><publisher><publisher-name>MDPI</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">31547294</article-id><article-id pub-id-type="pmc">6784133</article-id><article-id pub-id-type="doi">10.3390/toxins11090527</article-id><article-id pub-id-type="publisher-id">toxins-11-00527</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title><italic>Naja atra</italic> Cardiotoxin 3 Elicits Autophagy and Apoptosis in U937 Human Leukemia Cells through the Ca<sup>2+</sup>/PP2A/AMPK Axis</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Chiou</surname><given-names>Jing-Ting</given-names></name><xref ref-type="aff" rid="af1-toxins-11-00527">1</xref></contrib><contrib contrib-type="author"><name><surname>Shi</surname><given-names>Yi-Jun</given-names></name><xref ref-type="aff" rid="af1-toxins-11-00527">1</xref></contrib><contrib contrib-type="author"><name><surname>Wang</surname><given-names>Liang-Jun</given-names></name><xref ref-type="aff" rid="af1-toxins-11-00527">1</xref></contrib><contrib contrib-type="author"><name><surname>Huang</surname><given-names>Chia-Hui</given-names></name><xref ref-type="aff" rid="af1-toxins-11-00527">1</xref></contrib><contrib contrib-type="author"><name><surname>Lee</surname><given-names>Yuan-Chin</given-names></name><xref ref-type="aff" rid="af1-toxins-11-00527">1</xref></contrib><contrib contrib-type="author"><name><surname>Chang</surname><given-names>Long-Sen</given-names></name><xref ref-type="aff" rid="af1-toxins-11-00527">1</xref><xref ref-type="aff" rid="af2-toxins-11-00527">2</xref><xref rid="c1-toxins-11-00527" ref-type="corresp">*</xref></contrib></contrib-group><aff id="af1-toxins-11-00527"><label>1</label>Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan</aff><aff id="af2-toxins-11-00527"><label>2</label>Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 807, Taiwan</aff><author-notes><corresp id="c1-toxins-11-00527"><label>*</label>Correspondence: <email>lschang@mail.nsysu.edu.tw</email>; Tel.: +886-7-5252-000-5813</corresp></author-notes><pub-date pub-type="epub"><day>12</day><month>9</month><year>2019</year></pub-date><pub-date pub-type="collection"><month>9</month><year>2019</year></pub-date><volume>11</volume><issue>9</issue><elocation-id>527</elocation-id><history><date date-type="received"><day>23</day><month>8</month><year>2019</year></date><date date-type="accepted"><day>10</day><month>9</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>Cardiotoxins (CTXs) are suggested to exert their cytotoxicity through cell membrane damage. Other studies show that penetration of CTXs into cells elicits mitochondrial fragmentation or lysosome disruption, leading to cell death. Considering the role of AMPK-activated protein kinase (AMPK) in mitochondrial biogenesis and lysosomal biogenesis, we aimed to investigate whether the AMPK-mediated pathway modulated <italic>Naja atra</italic> (Taiwan cobra) CTX3 cytotoxicity in U937 human leukemia cells. Our results showed that CTX3 induced autophagy and apoptosis in U937 cells, whereas autophagic inhibitors suppressed CTX3-induced apoptosis. CTX3 treatment elicited Ca<sup>2+</sup>-dependent degradation of the protein phosphatase 2A (PP2A) catalytic subunit (PP2Acα) and phosphorylation of AMPKα. Overexpression of PP2Acα mitigated the CTX3-induced AMPKα phosphorylation. CTX3-induced autophagy was via AMPK-mediated suppression of the Akt/mTOR pathway. Removal of Ca<sup>2+</sup> or suppression of AMPKα phosphorylation inhibited the CTX3-induced cell death. CTX3 was unable to induce autophagy and apoptosis in U937 cells expressing constitutively active Akt. Met-modified CTX3 retained its membrane-perturbing activity, however, it did not induce AMPK activation and death of U937 cells. These results conclusively indicate that CTX3 induces autophagy and apoptosis in U937 cells via the Ca<sup>2+</sup>/PP2A/AMPK axis, and suggest that the membrane-perturbing activity of CTX3 is not crucial for the cell death signaling pathway induction.</p></abstract><kwd-group><kwd>cardiotoxin</kwd><kwd>Ca<sup>2+</sup></kwd><kwd>PP2A</kwd><kwd>AMPK</kwd><kwd>autophagy</kwd><kwd>apoptosis</kwd></kwd-group></article-meta><notes notes-type="Key Contribution"><title>Key Contribution</title><p>The cytotoxicity of <italic>N. atra</italic> CTX3 on U937 cells is related to the Ca<sup>2+</sup>/PP2A/AMPK axis-elicited autophagy and apoptosis; Our data suggest a dissociation of CTX3-induced death signaling from its effect on cell membrane damage.</p></notes></front><floats-group><fig id="toxins-11-00527-f001" orientation="portrait" position="float"><label>Figure 1</label><caption><p>Cobra cardiotoxin (CTX)3 induced apoptotic death of U937 cells. (<bold>A</bold>) Effect of CTX3 on the viability of U937 cells. Cells were incubated with indicated CTX3 concentrations for 4 h. (Inset) U937 cells were treated with 150 nM CTX3 for indicated time periods. Cell viability was determined using methlythiazolyldiphenyl-tetrazolium bromide (MTT) assay. Results are expressed as the percentage of cell survival relative to the control. Each value is the mean ± SD of three independent experiments with triplicate measurements; (<bold>B</bold>) Flow cytometry analyses of annexin V-PI double staining CTX3-treated cells. U937 cells were incubated with 150 nM CTX3 for 4 h. On the flow cytometric scatter graphs, the left lower quadrant represents remaining live cells. The right lower quadrant represents the population of early apoptotic cells. The right upper quadrant represents the accumulation of late apoptotic cells; (<bold>C</bold>) Western blot analyses of procaspase-3 and poly(ADP-ribose) polymerase (PARP) degradation in CTX3-treated cells. U937 cells were incubated with 150 nM CTX3 for 4 h; (<bold>D</bold>) Viability of CTX3-treated cells was restored by pretreatment with caspase inhibitors. U937 cells were pretreated with 10 μM Z-VAD-FMK (pan-caspase inhibitor) or Z-DEVD-FMK (caspase-3 inhibitor) for 1 h, and then incubated with 150 nM CTX3 for 4 h. Each value is the mean ± SD of three independent experiments with triplicate measurements (* <italic>p</italic> < 0.05).</p></caption><graphic xlink:href="toxins-11-00527-g001"></graphic></fig><fig id="toxins-11-00527-f002" orientation="portrait" position="float"><label>Figure 2</label><caption><p>CTX3-induced increase in [Ca<sup>2+</sup>]i elicited mitochondrial depolarization. Without specific indication, U937 cells were treated with 150 nM CTX3 for 4 h. (<bold>A</bold>) CTX3 induced dissipation of ΔΨm. The loss of ΔΨm was analyzed by flow cytometry.; (<bold>B</bold>) Western blot analyses of Bcl-2, Bcl-xL, and Mcl-1 in CTX3-treated U937 cells.; (<bold>C</bold>) CTX3 caused a reduction in mitochondrial mass.; (<bold>D</bold>) CTX3 induced an increase in [Ca<sup>2+</sup>]i. U937 cells were incubated with 150 nM CTX3 for indicated time periods. Results were shown as fold-increase in fluorescence intensity compared with the control group. Each value is the mean ± SD of three independent experiments with triplicate measurements. (<bold>E</bold>) Effect of BAPTA-AM on CTX3-induced increase in [Ca<sup>2+</sup>]i in U937 cells. U937 cells were pretreated with 10 μM BAPTA-AM for 1 h, and then incubated with 150 nM CTX3 for 4 h (mean ± SD, * <italic>p</italic> < 0.05).; (<bold>F</bold>) Effect of BAPTA-AM on the viability of CTX3-treated cells (mean ± SD, * <italic>p</italic> < 0.05). (<bold>G</bold>) Effect of BAPTA-AM on CTX3-induced the loss of ΔΨm (mean ± SD, * <italic>p</italic> < 0.05).</p></caption><graphic xlink:href="toxins-11-00527-g002"></graphic></fig><fig id="toxins-11-00527-f003" orientation="portrait" position="float"><label>Figure 3</label><caption><p>CTX3 induced autophagy of U937 cells. Without specific indication, U937 cells were treated with 150 nM CTX3 for 4 h. On the other hand, U937 cells were pre-treated with 10 μM BAPTA-AM, 10 μM 3-methyladenine (3-MA) or 10 μM chloroquine (CQ) for 1 h, and then incubated with 150 nM CTX3 for 4 h. (<bold>A</bold>) Western blot analyses of AMPKα and phospho-AMPKα in U937 cells; (<bold>B</bold>) Effect of BAPTA-AM on AMPKα phosphorylation; (<bold>C</bold>) Effect of CTX3 on LC3II and p62 expression; (<bold>D</bold>) Flow cytometry analysis of acidic vesicular organelles in cells treated with CTX3 or CQ plus CTX3. CTX3-treated cells were then stained with a Cyto-ID<sup>TM</sup> autophagy detection kit according to manufacturer’s protocol; (<bold>E</bold>) Effect of 3-MA and CQ on CTX3-induced the formation of LC3II and p62 downregulation; (<bold>F</bold>) Effect of 3-MA and CQ on the viability of CTX3-treated cells. Cell viability was determined using MTT assay (mean ± SD, * <italic>p</italic> < 0.05). (<bold>G</bold>) Effect of CQ on CTX3-induced apoptosis of U937 cells. Apoptosis was assessed in triplicate by annexin V-PI double staining followed by flow cytometry, and percentage apoptosis is shown as percentage of annexin V-positive cells. Data represent mean ± SD (* <italic>p</italic> < 0.05).</p></caption><graphic xlink:href="toxins-11-00527-g003"></graphic></fig><fig id="toxins-11-00527-f004" orientation="portrait" position="float"><label>Figure 4</label><caption><p>CTX3 induced phosphorylation of Akt, mTOR and S6R in U937 cells. Without specific indication, U937 cells were treated with 150 nM CTX3 for 4 h. (<bold>A</bold>) Effect of CTX3 on phosphorylation of Akt, mTOR, and S6R; (<bold>B</bold>) Effect of constitutively active Akt (CA-Akt) on the viability of CTX3-treated cells. U937 cells were transfected with empty expression vector or CA-Akt, respectively. After 24 h post-transfection, the transfected cells were treated with 150 nM CTX3 for 4 h. (Inset) Western blot analyses of Akt and phospho-Akt in CA-Akt-transfected cells; (<bold>C</bold>) Effect of CA-Akt on CTX3-induced apoptosis of U937 cells. Data represent mean ± SD (* <italic>p</italic> < 0.05). (<bold>D</bold>) Effect of CA-Akt on CTX3-induced the formation of LC3II and p62 downregulation.</p></caption><graphic xlink:href="toxins-11-00527-g004"></graphic></fig><fig id="toxins-11-00527-f005" orientation="portrait" position="float"><label>Figure 5</label><caption><p>CTX3-induced PP2Acα degradation promoted AMPKα phosphorylation. Without specific indication, U937 cells were treated with 150 nM CTX3 for 4 h. On the other hand, U937 cells were pre-treated with 1 μM MG132, 10 nM okadaic acid (OA) or 10 μM BAPTA-AM for 1 h, and then incubated with 150 nM CTX3 for 4 h. (<bold>A</bold>) Western blot analyses of PP2Acα expression in CTX3-treated cells; (<bold>B</bold>) Quantitative analyses of PP2Acα mRNA level in CTX3-treated cells; (<bold>C</bold>) Effect of MG132 on PP2Acα expression in CTX3-treated cells; (<bold>D</bold>) Effect of OA on CTX3-induced AMPKα phosphorylation. (<bold>E</bold>) Effect of PP2Acα overexpression on AMPKα phosphorylation in CTX3-treated cells. U937 cells were transfected with empty expression vector or pcDNA-PP2Acα, respectively. After 24 h post-transfection, the transfected cells were treated with 150 nM CTX3 for 4 h. (<bold>F</bold>) Effect of PP2Acα overexpression on the viability of CTX3-treated cells (mean ± SD, * <italic>p</italic> < 0.05). (<bold>G</bold>) Effect of BAPTA-AM on PP2Acα expression in CTX3-treated cells.</p></caption><graphic xlink:href="toxins-11-00527-g005"></graphic></fig><fig id="toxins-11-00527-f006" orientation="portrait" position="float"><label>Figure 6</label><caption><p>Effect of Met-modified CTX3 on AMPKα phosphorylation and membrane permeability of U937 cells. Without specific indication, U937 cells were treated with 150 nM CTX3 or Met-modified CTX3 for 4 h. (<bold>A</bold>) CTX3 and Met-modified CTX3 induced membrane permeability of EYPC/EYSM/cholesterol vesicles. Each value is the mean ± SD of three independent experiments with triplicate measurements; (<bold>B</bold>) Effect of Met-modified CTX3 on the viability of U937 cells. (<bold>C</bold>) Effect of Met-modified CTX3 on AMPKα phosphorylation in U937 cells; (<bold>D</bold>) CTX3 and Met-modified CTX3 induced the release of calcein from calcein-loaded U937 cells.</p></caption><graphic xlink:href="toxins-11-00527-g006"></graphic></fig><fig id="toxins-11-00527-f007" orientation="portrait" position="float"><label>Figure 7</label><caption><p>Effect of compound C on the cytotoxic effects of CTX3 on U937 cells. Without specific indication, U937 cells were pretreated with 0.5 μM compound C concentrations for 1 h, and then incubated with 150 nM CTX3 for 4 h. (<bold>A</bold>) Effect of compound C on AMPKα phosphorylation in U937 cells. U937 cells were pretreated with indicated compound C concentrations for 4 h. (<bold>B</bold>) Effect of compound C on the viability of CTX3-treated cells (mean ± SD, * <italic>p</italic> < 0.05). (<bold>C</bold>) Effect of compound C on AMPKα phosphorylation in CTX3-treated U937 cells.; (<bold>D</bold>) Effect of compound C on CTX3-induced reduction in mitochondrial mass. (<bold>E</bold>) Effect of compound C on CTX3-induced the loss of ΔΨm (mean ± SD, * <italic>p</italic> < 0.05). (<bold>F</bold>) Effect of compound C on CTX3-induced apoptosis of U937 cells (mean ± SD, * <italic>p</italic> < 0.05).</p></caption><graphic xlink:href="toxins-11-00527-g007"></graphic></fig></floats-group></pmc><affiliations><list><country><li>Taïwan</li></country></list><tree><country name="Taïwan"><noRegion><name sortKey="Chiou, Jing Ting" sort="Chiou, Jing Ting" uniqKey="Chiou J" first="Jing-Ting" last="Chiou">Jing-Ting Chiou</name></noRegion><name sortKey="Chang, Long Sen" sort="Chang, Long Sen" uniqKey="Chang L" first="Long-Sen" last="Chang">Long-Sen Chang</name><name sortKey="Chang, Long Sen" sort="Chang, Long Sen" uniqKey="Chang L" first="Long-Sen" last="Chang">Long-Sen Chang</name><name sortKey="Huang, Chia Hui" sort="Huang, Chia Hui" uniqKey="Huang C" first="Chia-Hui" last="Huang">Chia-Hui Huang</name><name sortKey="Lee, Yuan Chin" sort="Lee, Yuan Chin" uniqKey="Lee Y" first="Yuan-Chin" last="Lee">Yuan-Chin Lee</name><name sortKey="Shi, Yi Jun" sort="Shi, Yi Jun" uniqKey="Shi Y" first="Yi-Jun" last="Shi">Yi-Jun Shi</name><name sortKey="Wang, Liang Jun" sort="Wang, Liang Jun" uniqKey="Wang L" first="Liang-Jun" last="Wang">Liang-Jun Wang</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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