Apurinic endonuclease 1 promotes the cisplatin resistance of lung cancer cells by inducing Parkin-mediated mitophagy
Identifieur interne : 000A76 ( Ncbi/Merge ); précédent : 000A75; suivant : 000A77Apurinic endonuclease 1 promotes the cisplatin resistance of lung cancer cells by inducing Parkin-mediated mitophagy
Auteurs : Zheng Li [République populaire de Chine] ; Yongqiang Wang [République populaire de Chine] ; Linbo Wu [République populaire de Chine] ; Yalu Dong [République populaire de Chine] ; Jing Zhang [République populaire de Chine] ; Fan Chen [République populaire de Chine] ; Wei Xie [République populaire de Chine] ; Jianguo Huang [République populaire de Chine] ; Ning Lu [République populaire de Chine]Source :
- Oncology Reports [ 1021-335X ] ; 2019.
Abstract
Platinum-containing doublet chemotherapy is the cornerstone of lung cancer treatment; however, cisplatin resistance is a major obstacle in the treatment of lung cancer. However, the mechanism underlying this resistance has not been fully elucidated. Previous studies have shown that serum apurinic/apyrimidinic endonuclease 1 (APE1) levels in patients with NSCLC are inversely associated with progression-free survival after platinum-containing doublet chemotherapy, and can serve as a biomarker for predicting disease prognosis and treatment efficacy. The present study was designed to investigate the role played by APE1 in the resistance of lung cancer to cisplatin. The levels of mitochondrial apurinic endonuclease 1 (m-APE1) and total APE1 (t-APE1) protein in a cisplatin-resistant A549 cell line (A549/DDP) and cisplatin-sensitive A549 cells were analyzed by western blotting. Mitochondrial membrane potential was detected by using the JC-1 staining method. The cisplatin-resistance of APE1-overexpressing A549 cells and APE1-silenced A549/DDP cells was assessed by cell apoptosis and colony formation assays. The results revealed that cisplatin-resistant A549 cells contained high levels of APE1, and exhibited elevated levels of autophagy. The levels of m-APE1 and t-APE1 protein were increased in the A549/DDP cells when compared with these levels in the A549 cells. Overexpression of APE1 and Mia40 enhanced the cisplatin resistance and autophagy of the A549 cells. APE1 knockdown restored the cisplatin sensitivity and reduced the levels of LC3II and Parkin in the A549/DDP cells, but promoted the release of cytochrome
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DOI: 10.3892/or.2019.7345
PubMed: 31578585
PubMed Central: 6826301
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China</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>Cancer Center, Xinjiang Military Area General Hospital, Urumchi, Xinjiang Uygur Autonomous Region 830000</wicri:regionArea><wicri:noRegion>Xinjiang Uygur Autonomous Region 830000</wicri:noRegion></affiliation></author><author><name sortKey="Wang, Yongqiang" sort="Wang, Yongqiang" uniqKey="Wang Y" first="Yongqiang" last="Wang">Yongqiang Wang</name><affiliation wicri:level="1"><nlm:aff id="af1-or-0-0-7345">Cancer Center, Xinjiang Military Area General Hospital, Urumchi, Xinjiang Uygur Autonomous Region 830000, P.R. 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China</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>Cancer Center, Xinjiang Military Area General Hospital, Urumchi, Xinjiang Uygur Autonomous Region 830000</wicri:regionArea><wicri:noRegion>Xinjiang Uygur Autonomous Region 830000</wicri:noRegion></affiliation></author><author><name sortKey="Huang, Jianguo" sort="Huang, Jianguo" uniqKey="Huang J" first="Jianguo" last="Huang">Jianguo Huang</name><affiliation wicri:level="1"><nlm:aff id="af1-or-0-0-7345">Cancer Center, Xinjiang Military Area General Hospital, Urumchi, Xinjiang Uygur Autonomous Region 830000, P.R. China</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>Cancer Center, Xinjiang Military Area General Hospital, Urumchi, Xinjiang Uygur Autonomous Region 830000</wicri:regionArea><wicri:noRegion>Xinjiang Uygur Autonomous Region 830000</wicri:noRegion></affiliation></author><author><name sortKey="Lu, Ning" sort="Lu, Ning" uniqKey="Lu N" first="Ning" last="Lu">Ning Lu</name><affiliation wicri:level="1"><nlm:aff id="af1-or-0-0-7345">Cancer Center, Xinjiang Military Area General Hospital, Urumchi, Xinjiang Uygur Autonomous Region 830000, P.R. China</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>Cancer Center, Xinjiang Military Area General Hospital, Urumchi, Xinjiang Uygur Autonomous Region 830000</wicri:regionArea><wicri:noRegion>Xinjiang Uygur Autonomous Region 830000</wicri:noRegion></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">31578585</idno><idno type="pmc">6826301</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6826301</idno><idno type="RBID">PMC:6826301</idno><idno type="doi">10.3892/or.2019.7345</idno><date when="2019">2019</date><idno type="wicri:Area/Pmc/Corpus">000753</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000753</idno><idno type="wicri:Area/Pmc/Curation">000753</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000753</idno><idno type="wicri:Area/Pmc/Checkpoint">000995</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Checkpoint">000995</idno><idno type="wicri:Area/Ncbi/Merge">000A76</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Apurinic endonuclease 1 promotes the cisplatin resistance of lung cancer cells by inducing Parkin-mediated mitophagy</title><author><name sortKey="Li, Zheng" sort="Li, Zheng" uniqKey="Li Z" first="Zheng" last="Li">Zheng Li</name><affiliation wicri:level="1"><nlm:aff id="af1-or-0-0-7345">Cancer Center, Xinjiang Military Area General Hospital, Urumchi, Xinjiang Uygur Autonomous Region 830000, P.R. China</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>Cancer Center, Xinjiang Military Area General Hospital, Urumchi, Xinjiang Uygur Autonomous Region 830000</wicri:regionArea><wicri:noRegion>Xinjiang Uygur Autonomous Region 830000</wicri:noRegion></affiliation></author><author><name sortKey="Wang, Yongqiang" sort="Wang, Yongqiang" uniqKey="Wang Y" first="Yongqiang" last="Wang">Yongqiang Wang</name><affiliation wicri:level="1"><nlm:aff id="af1-or-0-0-7345">Cancer Center, Xinjiang Military Area General Hospital, Urumchi, Xinjiang Uygur Autonomous Region 830000, P.R. China</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>Cancer Center, Xinjiang Military Area General Hospital, Urumchi, Xinjiang Uygur Autonomous Region 830000</wicri:regionArea><wicri:noRegion>Xinjiang Uygur Autonomous Region 830000</wicri:noRegion></affiliation></author><author><name sortKey="Wu, Linbo" sort="Wu, Linbo" uniqKey="Wu L" first="Linbo" last="Wu">Linbo Wu</name><affiliation wicri:level="1"><nlm:aff id="af1-or-0-0-7345">Cancer Center, Xinjiang Military Area General Hospital, Urumchi, Xinjiang Uygur Autonomous Region 830000, P.R. China</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>Cancer Center, Xinjiang Military Area General Hospital, Urumchi, Xinjiang Uygur Autonomous Region 830000</wicri:regionArea><wicri:noRegion>Xinjiang Uygur Autonomous Region 830000</wicri:noRegion></affiliation></author><author><name sortKey="Dong, Yalu" sort="Dong, Yalu" uniqKey="Dong Y" first="Yalu" last="Dong">Yalu Dong</name><affiliation wicri:level="1"><nlm:aff id="af1-or-0-0-7345">Cancer Center, Xinjiang Military Area General Hospital, Urumchi, Xinjiang Uygur Autonomous Region 830000, P.R. China</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>Cancer Center, Xinjiang Military Area General Hospital, Urumchi, Xinjiang Uygur Autonomous Region 830000</wicri:regionArea><wicri:noRegion>Xinjiang Uygur Autonomous Region 830000</wicri:noRegion></affiliation></author><author><name sortKey="Zhang, Jing" sort="Zhang, Jing" uniqKey="Zhang J" first="Jing" last="Zhang">Jing Zhang</name><affiliation wicri:level="1"><nlm:aff id="af1-or-0-0-7345">Cancer Center, Xinjiang Military Area General Hospital, Urumchi, Xinjiang Uygur Autonomous Region 830000, P.R. China</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>Cancer Center, Xinjiang Military Area General Hospital, Urumchi, Xinjiang Uygur Autonomous Region 830000</wicri:regionArea><wicri:noRegion>Xinjiang Uygur Autonomous Region 830000</wicri:noRegion></affiliation></author><author><name sortKey="Chen, Fan" sort="Chen, Fan" uniqKey="Chen F" first="Fan" last="Chen">Fan Chen</name><affiliation wicri:level="1"><nlm:aff id="af1-or-0-0-7345">Cancer Center, Xinjiang Military Area General Hospital, Urumchi, Xinjiang Uygur Autonomous Region 830000, P.R. China</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>Cancer Center, Xinjiang Military Area General Hospital, Urumchi, Xinjiang Uygur Autonomous Region 830000</wicri:regionArea><wicri:noRegion>Xinjiang Uygur Autonomous Region 830000</wicri:noRegion></affiliation></author><author><name sortKey="Xie, Wei" sort="Xie, Wei" uniqKey="Xie W" first="Wei" last="Xie">Wei Xie</name><affiliation wicri:level="1"><nlm:aff id="af1-or-0-0-7345">Cancer Center, Xinjiang Military Area General Hospital, Urumchi, Xinjiang Uygur Autonomous Region 830000, P.R. China</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>Cancer Center, Xinjiang Military Area General Hospital, Urumchi, Xinjiang Uygur Autonomous Region 830000</wicri:regionArea><wicri:noRegion>Xinjiang Uygur Autonomous Region 830000</wicri:noRegion></affiliation></author><author><name sortKey="Huang, Jianguo" sort="Huang, Jianguo" uniqKey="Huang J" first="Jianguo" last="Huang">Jianguo Huang</name><affiliation wicri:level="1"><nlm:aff id="af1-or-0-0-7345">Cancer Center, Xinjiang Military Area General Hospital, Urumchi, Xinjiang Uygur Autonomous Region 830000, P.R. China</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>Cancer Center, Xinjiang Military Area General Hospital, Urumchi, Xinjiang Uygur Autonomous Region 830000</wicri:regionArea><wicri:noRegion>Xinjiang Uygur Autonomous Region 830000</wicri:noRegion></affiliation></author><author><name sortKey="Lu, Ning" sort="Lu, Ning" uniqKey="Lu N" first="Ning" last="Lu">Ning Lu</name><affiliation wicri:level="1"><nlm:aff id="af1-or-0-0-7345">Cancer Center, Xinjiang Military Area General Hospital, Urumchi, Xinjiang Uygur Autonomous Region 830000, P.R. China</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>Cancer Center, Xinjiang Military Area General Hospital, Urumchi, Xinjiang Uygur Autonomous Region 830000</wicri:regionArea><wicri:noRegion>Xinjiang Uygur Autonomous Region 830000</wicri:noRegion></affiliation></author></analytic><series><title level="j">Oncology Reports</title><idno type="ISSN">1021-335X</idno><idno type="eISSN">1791-2431</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>Platinum-containing doublet chemotherapy is the cornerstone of lung cancer treatment; however, cisplatin resistance is a major obstacle in the treatment of lung cancer. However, the mechanism underlying this resistance has not been fully elucidated. Previous studies have shown that serum apurinic/apyrimidinic endonuclease 1 (APE1) levels in patients with NSCLC are inversely associated with progression-free survival after platinum-containing doublet chemotherapy, and can serve as a biomarker for predicting disease prognosis and treatment efficacy. The present study was designed to investigate the role played by APE1 in the resistance of lung cancer to cisplatin. The levels of mitochondrial apurinic endonuclease 1 (m-APE1) and total APE1 (t-APE1) protein in a cisplatin-resistant A549 cell line (A549/DDP) and cisplatin-sensitive A549 cells were analyzed by western blotting. Mitochondrial membrane potential was detected by using the JC-1 staining method. The cisplatin-resistance of APE1-overexpressing A549 cells and APE1-silenced A549/DDP cells was assessed by cell apoptosis and colony formation assays. The results revealed that cisplatin-resistant A549 cells contained high levels of APE1, and exhibited elevated levels of autophagy. The levels of m-APE1 and t-APE1 protein were increased in the A549/DDP cells when compared with these levels in the A549 cells. Overexpression of APE1 and Mia40 enhanced the cisplatin resistance and autophagy of the A549 cells. APE1 knockdown restored the cisplatin sensitivity and reduced the levels of LC3II and Parkin in the A549/DDP cells, but promoted the release of cytochrome <italic>c</italic>. Furthermore, Parkin silencing or treatment with 3-methyladenine (3-MA, an autophagy inhibitor) promoted the apoptosis of APE1-overexpressing A549 cells, indicating that Parkin-mediated mitophagy plays an important role in the APE1-induced cisplatin resistance of A549 cells. In conclusion, APE1 promotes the cisplatin resistance of lung cancer cells by inducing Parkin-mediated mitophagy.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Jemal, A" uniqKey="Jemal A">A Jemal</name></author><author><name sortKey="Bray, F" uniqKey="Bray F">F Bray</name></author><author><name sortKey="Center, Mm" uniqKey="Center M">MM Center</name></author><author><name sortKey="Ferlay, J" uniqKey="Ferlay J">J Ferlay</name></author><author><name sortKey="Ward, E" uniqKey="Ward E">E Ward</name></author><author><name sortKey="Forman, D" uniqKey="Forman D">D Forman</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ren, J" uniqKey="Ren J">J Ren</name></author><author><name sortKey="Nie, Y" uniqKey="Nie Y">Y Nie</name></author><author><name sortKey="Lv, M" uniqKey="Lv M">M Lv</name></author><author><name sortKey="Shen, S" uniqKey="Shen S">S Shen</name></author><author><name sortKey="Tang, R" 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Oncol Rep</journal-id><journal-id journal-id-type="iso-abbrev">Oncol. Rep</journal-id><journal-title-group><journal-title>Oncology Reports</journal-title></journal-title-group><issn pub-type="ppub">1021-335X</issn><issn pub-type="epub">1791-2431</issn><publisher><publisher-name>D.A. Spandidos</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">31578585</article-id><article-id pub-id-type="pmc">6826301</article-id><article-id pub-id-type="doi">10.3892/or.2019.7345</article-id><article-id pub-id-type="publisher-id">OR-0-0-7345</article-id><article-categories><subj-group subj-group-type="heading"><subject>Articles</subject></subj-group></article-categories><title-group><article-title>Apurinic endonuclease 1 promotes the cisplatin resistance of lung cancer cells by inducing Parkin-mediated mitophagy</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Li</surname><given-names>Zheng</given-names></name><xref ref-type="aff" rid="af1-or-0-0-7345"></xref></contrib><contrib contrib-type="author"><name><surname>Wang</surname><given-names>Yongqiang</given-names></name><xref ref-type="aff" rid="af1-or-0-0-7345"></xref></contrib><contrib contrib-type="author"><name><surname>Wu</surname><given-names>Linbo</given-names></name><xref ref-type="aff" rid="af1-or-0-0-7345"></xref></contrib><contrib contrib-type="author"><name><surname>Dong</surname><given-names>Yalu</given-names></name><xref ref-type="aff" rid="af1-or-0-0-7345"></xref></contrib><contrib contrib-type="author"><name><surname>Zhang</surname><given-names>Jing</given-names></name><xref ref-type="aff" rid="af1-or-0-0-7345"></xref></contrib><contrib contrib-type="author"><name><surname>Chen</surname><given-names>Fan</given-names></name><xref ref-type="aff" rid="af1-or-0-0-7345"></xref></contrib><contrib contrib-type="author"><name><surname>Xie</surname><given-names>Wei</given-names></name><xref ref-type="aff" rid="af1-or-0-0-7345"></xref></contrib><contrib contrib-type="author"><name><surname>Huang</surname><given-names>Jianguo</given-names></name><xref ref-type="aff" rid="af1-or-0-0-7345"></xref></contrib><contrib contrib-type="author"><name><surname>Lu</surname><given-names>Ning</given-names></name><xref ref-type="aff" rid="af1-or-0-0-7345"></xref><xref rid="c1-or-0-0-7345" ref-type="corresp"></xref></contrib></contrib-group><aff id="af1-or-0-0-7345">Cancer Center, Xinjiang Military Area General Hospital, Urumchi, Xinjiang Uygur Autonomous Region 830000, P.R. China</aff><author-notes><corresp id="c1-or-0-0-7345"><italic>Correspondence to</italic>: Dr Ning Lu, Cancer Center, Xinjiang Military Area General Hospital, 359 Friendly North Road, Shayibake, Urumchi, Xinjiang Uygur Autonomous Region 830000, P.R. China, E-mail: <email>luning407@sina.com</email></corresp></author-notes><pub-date pub-type="ppub"><month>12</month><year>2019</year></pub-date><pub-date pub-type="epub"><day>01</day><month>10</month><year>2019</year></pub-date><pub-date pub-type="pmc-release"><day>01</day><month>10</month><year>2019</year></pub-date><pmc-comment> PMC Release delay is 0 months and 0 days and was based on the
<volume>42</volume><issue>6</issue><fpage>2245</fpage><lpage>2254</lpage><history><date date-type="received"><day>20</day><month>11</month><year>2018</year></date><date date-type="accepted"><day>16</day><month>7</month><year>2019</year></date></history><permissions><copyright-statement>Copyright: © Li et al.</copyright-statement><copyright-year>2019</copyright-year><license license-type="open-access"><license-p>This is an open access article distributed under the terms of the <ext-link ext-link-type="uri" xlink:href="https://creativecommons.org/licenses/by-nc-nd/4.0/">Creative Commons Attribution-NonCommercial-NoDerivs License</ext-link>, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.</license-p></license></permissions><abstract><p>Platinum-containing doublet chemotherapy is the cornerstone of lung cancer treatment; however, cisplatin resistance is a major obstacle in the treatment of lung cancer. However, the mechanism underlying this resistance has not been fully elucidated. Previous studies have shown that serum apurinic/apyrimidinic endonuclease 1 (APE1) levels in patients with NSCLC are inversely associated with progression-free survival after platinum-containing doublet chemotherapy, and can serve as a biomarker for predicting disease prognosis and treatment efficacy. The present study was designed to investigate the role played by APE1 in the resistance of lung cancer to cisplatin. The levels of mitochondrial apurinic endonuclease 1 (m-APE1) and total APE1 (t-APE1) protein in a cisplatin-resistant A549 cell line (A549/DDP) and cisplatin-sensitive A549 cells were analyzed by western blotting. Mitochondrial membrane potential was detected by using the JC-1 staining method. The cisplatin-resistance of APE1-overexpressing A549 cells and APE1-silenced A549/DDP cells was assessed by cell apoptosis and colony formation assays. The results revealed that cisplatin-resistant A549 cells contained high levels of APE1, and exhibited elevated levels of autophagy. The levels of m-APE1 and t-APE1 protein were increased in the A549/DDP cells when compared with these levels in the A549 cells. Overexpression of APE1 and Mia40 enhanced the cisplatin resistance and autophagy of the A549 cells. APE1 knockdown restored the cisplatin sensitivity and reduced the levels of LC3II and Parkin in the A549/DDP cells, but promoted the release of cytochrome <italic>c</italic>. Furthermore, Parkin silencing or treatment with 3-methyladenine (3-MA, an autophagy inhibitor) promoted the apoptosis of APE1-overexpressing A549 cells, indicating that Parkin-mediated mitophagy plays an important role in the APE1-induced cisplatin resistance of A549 cells. In conclusion, APE1 promotes the cisplatin resistance of lung cancer cells by inducing Parkin-mediated mitophagy.</p></abstract><kwd-group><kwd>lung cancer</kwd><kwd>APE1</kwd><kwd>cisplatin resistance</kwd><kwd>mitophagy</kwd><kwd>autophagy</kwd></kwd-group></article-meta></front><floats-group><fig id="f1-or-0-0-7345" orientation="portrait" position="float"><label>Figure 1.</label><caption><p>Cisplatin-resistant A549 cells exhibit high levels of APE1 and autophagy. (A) A549 cells were treated with 0, 1, 2, 3, 4, 5 and 6 µmol/l cisplatin for 24 h, and the A549/DDP cells were treated with 0, 10, 20, 30, 40, 50 and 60 µmol/l cisplatin for 24 h. Cell viability was assessed by the CCK-8 assay. (B) Western blot analysis was performed to analyze the levels of mitochondrial APE1 (m-APE1) protein in A549/DDP and A549 cells. COX4 was used as loading control for the mitochondrial APE1 protein. (C) Western blot analysis of the total APE1 (t-APE1) and Mia40 protein levels in A549/DDP and A549 cells. GAPDH was used as a loading control. (D) Western blot analysis of the LC3 protein levels in A549/DDP and A549 cells. (E and F) Immunofluorescence assays were performed to assess the total APE1 and total LC3 levels in A549 and A549/DDP cells. Data represent results obtained from three independent experiments (mean ± SEM of triplicate samples). ***P<0.001, vs. 0 µmol/l cisplatin-treated A549 or A549/DDP cells. APE1, apurinic/apyrimidinic endonuclease 1; LC3, microtubule-associated protein 1A/1B-light chain 3.</p></caption><graphic xlink:href="or-42-06-2245-g00"></graphic></fig><fig id="f2-or-0-0-7345" orientation="portrait" position="float"><label>Figure 2.</label><caption><p>APE1 and Mia40 overexpression increases the cisplatin resistance of A549 cells. A549 cells were transfected with vectors containing an APE1 overexpression plasmid and Mia40 overexpression plasmid as indicated. (A) Transfection efficiency was assessed by qPCR. (B) Western blot analysis of the mitochondrial APE1 (m-APE1) protein levels in A549 cells after transfection. COX4 was used as loading control for mitochondrial APE1. (C) Western blot analysis was used to analyze the total APE1 (t-APE1) and Mia40 protein levels in A549 cells after transfection. GAPDH was used as a loading control. (D) Immunofluorescence assays were performed to assess the total APE1 levels in A549 cells after transfection. (E) The transfected A549 cells were treated with 0, 1, 2, 3, 4, 5, and 6 µmol/l cisplatin for 24 h, and their viability was assessed by the CCK-8 assay. (F) Colony-formation assays were performed to analyze the colony formation efficiency of the transfected A549 cells. *P<0.05, ***P<0.001, vs. the vector group. <sup>#</sup>P<0.05, vs. the APE1 group. APE1, apurinic/apyrimidinic endonuclease 1; LC3, microtubule-associated protein 1A/1B-light chain 3. (G) Flow cytometry was used to analyze the cellular distribution of JC-1 after transfection. (H) Transfected A549 cells were treated with cisplatin, and their rate of apoptosis was analyzed by flow cytometry. (I) The transfected A549 cells were subjected to fractionation to obtain the cytosolic fraction. Western blot analysis was performed to analyze the levels of LC3, total cytochrome <italic>c</italic>, and Parkin in the transfected A549 cells. (J) The cell apoptosis rate is shown in a histogram. GAPDH was used as loading control. Data represent results obtained from three independent experiments (mean ± SEM of triplicate samples). ****P<0.0001 vs. the vector group. APE1, apurinic/apyrimidinic endonuclease 1; LC3, microtubule-associated protein 1A/1B-light chain 3.</p></caption><graphic xlink:href="or-42-06-2245-g01"></graphic><graphic xlink:href="or-42-06-2245-g02"></graphic></fig><fig id="f3-or-0-0-7345" orientation="portrait" position="float"><label>Figure 3.</label><caption><p>APE1 knockdown increases the cisplatin sensitivity of A549/DDP cells. A549/DDP cells were transfected with small interfering RNA (si-APE1 or si-NC). (A) Transfection efficiency was assessed by qPCR. (B) The levels of mitochondrial APE1 (m-APE1) in the transfected A549/DDP cells were analyzed by western blotting. COX4 was used as loading control for mitochondrial APE1. (C) The total APE1 (t-APE1) protein levels in transfected A549/DDP cells were analyzed by western blotting. GAPDH was used as loading control. (D) Immunofluorescence assays were performed to assess the total APE1 levels in A549/DDP cells after transfection. (E) Transfected A549/DDP cells were treated with 15 µmol/l cisplatin for 24 h, and their viability was assessed by the CCK-8 assay. (F) Colony formation assays were performed to analyze the colony formation efficiency of the transfected A549/DDP cells. (G) The transfected A549/DDP cells were treated with cisplatin, and their rate of apoptosis was analyzed by flow cytometry. (H) Flow cytometry was used to analyze the distribution of JC-1 after transfection. (I) The transfected A549/DDP cells were subjected to fractionation to obtain the cytosolic fraction. Western blot analysis was performed to analyze the levels of LC3, total cytochrome <italic>c</italic>, and Parkin. (J) The cell apoptosis rate is shown in a histogram. GAPDH was used as loading control. Data represent the results obtained from three independent experiments (mean ± SEM of triplicate samples). *P<0.05, ***P<0.001 and ****P<0.0001 vs. the si-NC group. APE1, apurinic/apyrimidinic endonuclease 1; LC3, microtubule-associated protein 1A/1B-light chain 3.</p></caption><graphic xlink:href="or-42-06-2245-g03"></graphic></fig><fig id="f4-or-0-0-7345" orientation="portrait" position="float"><label>Figure 4.</label><caption><p>Parkin-mediated mitophagy plays an important role in the APE1-induced cisplatin resistance of A549 cells. A549 cells were first transfected with an APE1 overexpression plasmid. Next, the APE1-overexpressing A549 cells were transfected with small interfering RNA (si-Parkin or si-NC) or treated with 3-MA. (A) A549 cells after the relevant transfections (APE1, si-Parkin or si-NC) and their indicated treatment were subjected to fractionation to obtain the cytosolic fraction. Western blot analysis was performed to analyze the levels of LC3, total cytochrome <italic>c</italic>, and Parkin in the cytosolic fraction. GAPDH was used as loading control. (B) Following the indicated transfection and treatment, the A549 cells were co-cultured with 3 µmol/l cisplatin for 24 h, and their viability was assessed by the CCK-8 assay. (C) Colony formation assays were performed to analyze the colony formation efficiency of the transfected A549 cells after they had received their indicated treatment. (D) The cell apoptosis rates are shown in a histogram. (E) The apoptosis rates of the transfected A549 cells treated or not with 3-MA were analyzed by flow cytometry. (F) The distribution of JC-1 in the transfected A549 cells was analyzed by flow cytometry. *P<0.05 and ****P<0.0001 vs. the APE1 group. 3-MA, 3-methyladenine (an autophagy inhibitor); APE1, apurinic/apyrimidinic endonuclease 1; LC3, microtubule-associated protein 1A/1B-light chain 3.</p></caption><graphic xlink:href="or-42-06-2245-g04"></graphic></fig><fig id="f5-or-0-0-7345" orientation="portrait" position="float"><label>Figure 5.</label><caption><p>A schematic diagram showing how APE1 functions in the signaling circuit involved in lung cancer cisplatin resistance. APE1, apurinic/apyrimidinic endonuclease 1; LC3, microtubule-associated protein 1A/1B-light chain 3.</p></caption><graphic xlink:href="or-42-06-2245-g05"></graphic></fig></floats-group></pmc><affiliations><list><country><li>République populaire de Chine</li></country></list><tree><country name="République populaire de Chine"><noRegion><name sortKey="Li, Zheng" sort="Li, Zheng" uniqKey="Li Z" first="Zheng" last="Li">Zheng Li</name></noRegion><name sortKey="Chen, Fan" sort="Chen, Fan" uniqKey="Chen F" first="Fan" last="Chen">Fan Chen</name><name sortKey="Dong, Yalu" sort="Dong, Yalu" uniqKey="Dong Y" first="Yalu" last="Dong">Yalu Dong</name><name sortKey="Huang, Jianguo" sort="Huang, Jianguo" uniqKey="Huang J" first="Jianguo" last="Huang">Jianguo Huang</name><name sortKey="Lu, Ning" sort="Lu, Ning" uniqKey="Lu N" first="Ning" last="Lu">Ning Lu</name><name sortKey="Wang, Yongqiang" sort="Wang, Yongqiang" uniqKey="Wang Y" first="Yongqiang" last="Wang">Yongqiang Wang</name><name sortKey="Wu, Linbo" sort="Wu, Linbo" uniqKey="Wu L" first="Linbo" last="Wu">Linbo Wu</name><name sortKey="Xie, Wei" sort="Xie, Wei" uniqKey="Xie W" first="Wei" last="Xie">Wei Xie</name><name sortKey="Zhang, Jing" sort="Zhang, Jing" uniqKey="Zhang J" first="Jing" last="Zhang">Jing Zhang</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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