Docosahexaenoic Acid Enhances Oxaliplatin-Induced Autophagic Cell Death via the ER Stress/Sesn2 Pathway in Colorectal Cancer
Identifieur interne : 000818 ( Pmc/Checkpoint ); précédent : 000817; suivant : 000819Docosahexaenoic Acid Enhances Oxaliplatin-Induced Autophagic Cell Death via the ER Stress/Sesn2 Pathway in Colorectal Cancer
Auteurs : Soyeon Jeong [Corée du Sud] ; Dae Yeong Kim [Corée du Sud] ; Sang Hee Kang [Corée du Sud] ; Hye Kyeong Yun [Corée du Sud] ; Jung Lim Kim [Corée du Sud] ; Bo Ram Kim [Corée du Sud] ; Seong Hye Park [Corée du Sud] ; Yoo Jin Na [Corée du Sud] ; Min Jee Jo [Corée du Sud] ; Yoon A. Jeong [Corée du Sud] ; Bu Gyeom Kim [Corée du Sud] ; Dae-Hee Lee [Corée du Sud] ; Sang Cheul Oh [Corée du Sud]Source :
- Cancers [ 2072-6694 ] ; 2019.
Abstract
Oxaliplatin is an anticancer drug administered to colorectal cancer (CRC) patients in combination with 5-fluorouracil and antibodies (bevacizumab and cetuximab), thereby significantly improving the survival rate of CRC. However, due to various side effects associated with the above treatment strategy, the need for combinatorial therapeutic strategies has emerged. Based on the demand for new combinatorial therapies and the known antitumor effects of the omega-3 polyunsaturated fatty acid, docosahexaenoic acid (DHA), we investigated the Oxaliplatin and DHA combination for its effect. Our results indicated that DHA further enhanced Oxaliplatin-induced cell viability and autophagic cell death, in vitro and in vivo. Oxaliplatin and DHA also increased the expression of Sestrin 2 (SESN2) and endoplasmic reticulum (ER) stress related C/EBP homologous protein (CHOP). Additionally, treatment with Oxaliplatin and DHA enhanced the binding of CHOP to the promotor region of SESN2, increasing SESN2 expression. These results suggested that DHA enhanced Oxaliplatin-induced reduction in cell viability and increase in autophagy via activating SESN2 and increasing ER stress. Thus, SESN2 may be an effective preclinical target for CRC treatment.
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DOI: 10.3390/cancers11070982
PubMed: 31337142
PubMed Central: 6678695
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last="Kim">Dae Yeong Kim</name><affiliation wicri:level="1"><nlm:aff id="af2-cancers-11-00982">Graduate School of Medicine, College of Medicine, Korea University, Seoul 08308, Korea</nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea>Graduate School of Medicine, College of Medicine, Korea University, Seoul 08308</wicri:regionArea><placeName><settlement type="city">Séoul</settlement><region type="capital">Région capitale de Séoul</region></placeName></affiliation></author><author><name sortKey="Kang, Sang Hee" sort="Kang, Sang Hee" uniqKey="Kang S" first="Sang Hee" last="Kang">Sang Hee Kang</name><affiliation wicri:level="1"><nlm:aff id="af3-cancers-11-00982">Department of Surgery, Korea University Guro Hospital, Korea University College of Medicine, Seoul 08308, Korea</nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea>Department of Surgery, Korea University Guro Hospital, Korea University College of Medicine, Seoul 08308</wicri:regionArea><placeName><settlement type="city">Séoul</settlement><region type="capital">Région capitale de Séoul</region></placeName></affiliation></author><author><name sortKey="Yun, Hye Kyeong" sort="Yun, Hye Kyeong" uniqKey="Yun H" first="Hye Kyeong" last="Yun">Hye Kyeong Yun</name><affiliation wicri:level="1"><nlm:aff id="af2-cancers-11-00982">Graduate School of Medicine, College of Medicine, Korea University, Seoul 08308, Korea</nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea>Graduate School of Medicine, College of Medicine, Korea University, Seoul 08308</wicri:regionArea><placeName><settlement type="city">Séoul</settlement><region type="capital">Région capitale de Séoul</region></placeName></affiliation></author><author><name sortKey="Kim, Jung Lim" sort="Kim, Jung Lim" uniqKey="Kim J" first="Jung Lim" last="Kim">Jung Lim Kim</name><affiliation wicri:level="1"><nlm:aff id="af1-cancers-11-00982">Department of Oncology, Korea University Guro 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Séoul</region></placeName></affiliation></author><author><name sortKey="Park, Seong Hye" sort="Park, Seong Hye" uniqKey="Park S" first="Seong Hye" last="Park">Seong Hye Park</name><affiliation wicri:level="1"><nlm:aff id="af2-cancers-11-00982">Graduate School of Medicine, College of Medicine, Korea University, Seoul 08308, Korea</nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea>Graduate School of Medicine, College of Medicine, Korea University, Seoul 08308</wicri:regionArea><placeName><settlement type="city">Séoul</settlement><region type="capital">Région capitale de Séoul</region></placeName></affiliation></author><author><name sortKey="Na, Yoo Jin" sort="Na, Yoo Jin" uniqKey="Na Y" first="Yoo Jin" last="Na">Yoo Jin Na</name><affiliation wicri:level="1"><nlm:aff id="af2-cancers-11-00982">Graduate School of Medicine, College of Medicine, Korea University, Seoul 08308, Korea</nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea>Graduate School of Medicine, College of Medicine, Korea University, Seoul 08308</wicri:regionArea><placeName><settlement type="city">Séoul</settlement><region type="capital">Région capitale de Séoul</region></placeName></affiliation></author><author><name sortKey="Jo, Min Jee" sort="Jo, Min Jee" uniqKey="Jo M" first="Min Jee" last="Jo">Min Jee Jo</name><affiliation wicri:level="1"><nlm:aff id="af2-cancers-11-00982">Graduate School of Medicine, College of Medicine, Korea University, Seoul 08308, Korea</nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea>Graduate School of Medicine, College of Medicine, Korea University, Seoul 08308</wicri:regionArea><placeName><settlement type="city">Séoul</settlement><region type="capital">Région capitale de Séoul</region></placeName></affiliation></author><author><name sortKey="Jeong, Yoon A" sort="Jeong, Yoon A" uniqKey="Jeong Y" first="Yoon A." last="Jeong">Yoon A. Jeong</name><affiliation wicri:level="1"><nlm:aff id="af2-cancers-11-00982">Graduate School of Medicine, College of Medicine, Korea University, Seoul 08308, Korea</nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea>Graduate School of Medicine, College of Medicine, Korea University, Seoul 08308</wicri:regionArea><placeName><settlement type="city">Séoul</settlement><region type="capital">Région capitale de Séoul</region></placeName></affiliation></author><author><name sortKey="Kim, Bu Gyeom" sort="Kim, Bu Gyeom" uniqKey="Kim B" first="Bu Gyeom" last="Kim">Bu Gyeom Kim</name><affiliation wicri:level="1"><nlm:aff id="af2-cancers-11-00982">Graduate School of Medicine, College of Medicine, Korea University, Seoul 08308, Korea</nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea>Graduate School of Medicine, College of Medicine, Korea University, Seoul 08308</wicri:regionArea><placeName><settlement type="city">Séoul</settlement><region type="capital">Région capitale de Séoul</region></placeName></affiliation></author><author><name sortKey="Lee, Dae Hee" sort="Lee, Dae Hee" uniqKey="Lee D" first="Dae-Hee" last="Lee">Dae-Hee Lee</name><affiliation wicri:level="1"><nlm:aff id="af1-cancers-11-00982">Department of Oncology, Korea University Guro Hospital, Korea University College of Medicine, Seoul 08308, Korea</nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea>Department of Oncology, Korea University Guro Hospital, Korea University College of Medicine, Seoul 08308</wicri:regionArea><placeName><settlement type="city">Séoul</settlement><region type="capital">Région capitale de Séoul</region></placeName></affiliation><affiliation wicri:level="1"><nlm:aff id="af2-cancers-11-00982">Graduate School of Medicine, College of Medicine, Korea University, Seoul 08308, Korea</nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea>Graduate School of Medicine, College of Medicine, Korea University, Seoul 08308</wicri:regionArea><placeName><settlement type="city">Séoul</settlement><region type="capital">Région capitale de Séoul</region></placeName></affiliation></author><author><name sortKey="Oh, Sang Cheul" sort="Oh, Sang Cheul" uniqKey="Oh S" first="Sang Cheul" last="Oh">Sang Cheul Oh</name><affiliation wicri:level="1"><nlm:aff id="af1-cancers-11-00982">Department of Oncology, Korea University Guro Hospital, Korea University College of Medicine, Seoul 08308, Korea</nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea>Department of Oncology, Korea University Guro Hospital, Korea University College of Medicine, Seoul 08308</wicri:regionArea><placeName><settlement type="city">Séoul</settlement><region type="capital">Région capitale de Séoul</region></placeName></affiliation><affiliation wicri:level="1"><nlm:aff id="af2-cancers-11-00982">Graduate School of Medicine, College of Medicine, Korea University, Seoul 08308, Korea</nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea>Graduate School of Medicine, College of Medicine, Korea University, Seoul 08308</wicri:regionArea><placeName><settlement type="city">Séoul</settlement><region type="capital">Région capitale de Séoul</region></placeName></affiliation></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>Oxaliplatin is an anticancer drug administered to colorectal cancer (CRC) patients in combination with 5-fluorouracil and antibodies (bevacizumab and cetuximab), thereby significantly improving the survival rate of CRC. However, due to various side effects associated with the above treatment strategy, the need for combinatorial therapeutic strategies has emerged. Based on the demand for new combinatorial therapies and the known antitumor effects of the omega-3 polyunsaturated fatty acid, docosahexaenoic acid (DHA), we investigated the Oxaliplatin and DHA combination for its effect. Our results indicated that DHA further enhanced Oxaliplatin-induced cell viability and autophagic cell death, in vitro and in vivo. Oxaliplatin and DHA also increased the expression of Sestrin 2 (SESN2) and endoplasmic reticulum (ER) stress related C/EBP homologous protein (CHOP). Additionally, treatment with Oxaliplatin and DHA enhanced the binding of CHOP to the promotor region of SESN2, increasing SESN2 expression. These results suggested that DHA enhanced Oxaliplatin-induced reduction in cell viability and increase in autophagy via activating SESN2 and increasing ER stress. Thus, SESN2 may be an effective preclinical target for CRC treatment.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Siegel, R L" uniqKey="Siegel R">R.L. Siegel</name></author><author><name sortKey="Miller, K D" uniqKey="Miller K">K.D. Miller</name></author><author><name sortKey="Jemal, A" uniqKey="Jemal A">A. Jemal</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Bendell, J C" uniqKey="Bendell J">J.C. Bendell</name></author><author><name sortKey="Bekaii Saab, T S" uniqKey="Bekaii Saab T">T.S. Bekaii-Saab</name></author><author><name sortKey="Cohn, A L" uniqKey="Cohn A">A.L. Cohn</name></author><author><name sortKey="Hurwitz, H I" uniqKey="Hurwitz H">H.I. Hurwitz</name></author><author><name sortKey="Kozloff, M" uniqKey="Kozloff M">M. Kozloff</name></author><author><name sortKey="Tezcan, H" uniqKey="Tezcan H">H. Tezcan</name></author><author><name sortKey="Roach, N" uniqKey="Roach 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">31337142</article-id><article-id pub-id-type="pmc">6678695</article-id><article-id pub-id-type="doi">10.3390/cancers11070982</article-id><article-id pub-id-type="publisher-id">cancers-11-00982</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Docosahexaenoic Acid Enhances Oxaliplatin-Induced Autophagic Cell Death via the ER Stress/Sesn2 Pathway in Colorectal Cancer</article-title></title-group><contrib-group><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0002-4568-4579</contrib-id><name><surname>Jeong</surname><given-names>Soyeon</given-names></name><xref ref-type="aff" rid="af1-cancers-11-00982">1</xref><xref ref-type="author-notes" rid="fn1-cancers-11-00982">†</xref></contrib><contrib contrib-type="author"><name><surname>Kim</surname><given-names>Dae Yeong</given-names></name><xref ref-type="aff" rid="af2-cancers-11-00982">2</xref><xref ref-type="author-notes" rid="fn1-cancers-11-00982">†</xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0002-6097-8831</contrib-id><name><surname>Kang</surname><given-names>Sang Hee</given-names></name><xref ref-type="aff" rid="af3-cancers-11-00982">3</xref></contrib><contrib contrib-type="author"><name><surname>Yun</surname><given-names>Hye Kyeong</given-names></name><xref ref-type="aff" rid="af2-cancers-11-00982">2</xref></contrib><contrib contrib-type="author"><name><surname>Kim</surname><given-names>Jung Lim</given-names></name><xref ref-type="aff" rid="af1-cancers-11-00982">1</xref></contrib><contrib contrib-type="author"><name><surname>Kim</surname><given-names>Bo Ram</given-names></name><xref ref-type="aff" rid="af1-cancers-11-00982">1</xref></contrib><contrib contrib-type="author"><name><surname>Park</surname><given-names>Seong Hye</given-names></name><xref ref-type="aff" rid="af2-cancers-11-00982">2</xref></contrib><contrib contrib-type="author"><name><surname>Na</surname><given-names>Yoo Jin</given-names></name><xref ref-type="aff" rid="af2-cancers-11-00982">2</xref></contrib><contrib contrib-type="author"><name><surname>Jo</surname><given-names>Min Jee</given-names></name><xref ref-type="aff" rid="af2-cancers-11-00982">2</xref></contrib><contrib contrib-type="author"><name><surname>Jeong</surname><given-names>Yoon A.</given-names></name><xref ref-type="aff" rid="af2-cancers-11-00982">2</xref></contrib><contrib contrib-type="author"><name><surname>Kim</surname><given-names>Bu Gyeom</given-names></name><xref ref-type="aff" rid="af2-cancers-11-00982">2</xref></contrib><contrib contrib-type="author"><name><surname>Lee</surname><given-names>Dae-Hee</given-names></name><xref ref-type="aff" rid="af1-cancers-11-00982">1</xref><xref ref-type="aff" rid="af2-cancers-11-00982">2</xref><xref rid="c1-cancers-11-00982" ref-type="corresp">*</xref></contrib><contrib contrib-type="author"><name><surname>Oh</surname><given-names>Sang Cheul</given-names></name><xref ref-type="aff" rid="af1-cancers-11-00982">1</xref><xref ref-type="aff" rid="af2-cancers-11-00982">2</xref><xref rid="c1-cancers-11-00982" ref-type="corresp">*</xref></contrib></contrib-group><aff id="af1-cancers-11-00982"><label>1</label>Department of Oncology, Korea University Guro Hospital, Korea University College of Medicine, Seoul 08308, Korea</aff><aff id="af2-cancers-11-00982"><label>2</label>Graduate School of Medicine, College of Medicine, Korea University, Seoul 08308, Korea</aff><aff id="af3-cancers-11-00982"><label>3</label>Department of Surgery, Korea University Guro Hospital, Korea University College of Medicine, Seoul 08308, Korea</aff><author-notes><corresp id="c1-cancers-11-00982"><label>*</label>Correspondence: <email>neogene@korea.ac.kr</email> (D.-H.L.); <email>sachoh@korea.ac.kr</email> (S.C.O.); Tel.: +82-2-2626-1147 (D.-H.L. & S.C.O.); Fax: +82-2-2626-1148 (D.-H.L. & S.C.O.)</corresp><fn id="fn1-cancers-11-00982"><label>†</label><p>These authors contributed equally to this work.</p></fn></author-notes><pub-date pub-type="epub"><day>14</day><month>7</month><year>2019</year></pub-date><pub-date pub-type="collection"><month>7</month><year>2019</year></pub-date><volume>11</volume><issue>7</issue><elocation-id>982</elocation-id><history><date date-type="received"><day>07</day><month>5</month><year>2019</year></date><date date-type="accepted"><day>08</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>Oxaliplatin is an anticancer drug administered to colorectal cancer (CRC) patients in combination with 5-fluorouracil and antibodies (bevacizumab and cetuximab), thereby significantly improving the survival rate of CRC. However, due to various side effects associated with the above treatment strategy, the need for combinatorial therapeutic strategies has emerged. Based on the demand for new combinatorial therapies and the known antitumor effects of the omega-3 polyunsaturated fatty acid, docosahexaenoic acid (DHA), we investigated the Oxaliplatin and DHA combination for its effect. Our results indicated that DHA further enhanced Oxaliplatin-induced cell viability and autophagic cell death, in vitro and in vivo. Oxaliplatin and DHA also increased the expression of Sestrin 2 (SESN2) and endoplasmic reticulum (ER) stress related C/EBP homologous protein (CHOP). Additionally, treatment with Oxaliplatin and DHA enhanced the binding of CHOP to the promotor region of SESN2, increasing SESN2 expression. These results suggested that DHA enhanced Oxaliplatin-induced reduction in cell viability and increase in autophagy via activating SESN2 and increasing ER stress. Thus, SESN2 may be an effective preclinical target for CRC treatment.</p></abstract><kwd-group><kwd>Oxaliplatin</kwd><kwd>docosahexaenoic acid</kwd><kwd>Sestrin 2</kwd><kwd>autophagic cell death</kwd><kwd>colon cancer</kwd></kwd-group></article-meta></front><floats-group><fig id="cancers-11-00982-f001" orientation="portrait" position="float"><label>Figure 1</label><caption><p>Combinatorial treatment with Oxaliplatin and docosahexaenoic acid (DHA) reduces viability and induces cell death in human colorectal cancer (CRC) cells. (<bold>A</bold>) Human normal colon CCD-18Co cells and various human CRC cells were treated with 0–60 µM of DHA for 24 h. Cell viability was measured via a WST-1 assay. ***, <italic>p</italic> < 0.001; (<bold>B</bold>) HCT116 cells were treated with 0–60 µM of ω3-polyunsaturated fatty acids (PUFAs) or ω6-PUFAs for 24 h. Cell viability was determined via a WST-1 assay; (<bold>C</bold>) Combination index (CI) for Oxaliplatin and DHA; (<bold>D</bold>) CRC cells were treated with the indicated doses of Oxaliplatin and DHA for 24 h. Cell viability was determined via the WST-1 assay. ***, <italic>p</italic> < 0.001; (<bold>E</bold>) Cell death was measured via Annexin V/propidium iodide staining using flow cytometry in HCT116 cells. ***, <italic>p</italic> < 0.001; (<bold>F</bold>) Intensity of bioluminescence after treatment with Oxaliplatin and DHA in the HCT116 Luc<sup>+</sup> cells. The captured images were quantified using Image J. ***, <italic>p</italic> < 0.001.</p></caption><graphic xlink:href="cancers-11-00982-g001"></graphic></fig><fig id="cancers-11-00982-f002" orientation="portrait" position="float"><label>Figure 2</label><caption><p>DHA enhances Oxaliplatin-induced autophagy in human CRC cells. (<bold>A</bold>,<bold>B</bold>) HCT116 cells were subjected to indicated doses (<bold>A</bold>) and time (<bold>B</bold>) periods for 24 h. Then, the protein level of microtubule-associated protein 1A/1B-light chain 3 (LC3) and p62 were analyzed by immunoblotting. (<bold>C</bold>) Formation of green fluorescence protein (GFP)-LC3 puncta following exposure to Oxaliplatin and DHA was analyzed using confocal microscopy (Scale Bar, 10 μm). (<bold>D</bold>,<bold>E</bold>) HCT116 cells were treated with Oxaliplatin and DHA in the absence or presence of chloroquine (CQ) or rapamycin for 24, and 48 h. Autophagic cells (<bold>D</bold>), and autophagic markers (<bold>E</bold>) were detected using immunoblotting and a flow cytometer with an autophagy detection kit.</p></caption><graphic xlink:href="cancers-11-00982-g002"></graphic></fig><fig id="cancers-11-00982-f003" orientation="portrait" position="float"><label>Figure 3</label><caption><p>Combinatorial treatment upregulates expression of SESN2 in human CRC. (<bold>A</bold>) mRNA expression levels of SESN2 in normal and tumor tissues were evaluated using the mRNA expression data of the IlluminaHiSeq of TCGA CRC. **, <italic>p</italic> < 0.01. (<bold>B</bold>) SESN2 protein levels in normal and tumor tissues were evaluated using western blotting. (<bold>C</bold>,<bold>D</bold>) Comparison of endogenous expression levels of SESN2 mRNA and protein in normal human cells and human CRC cells using quantitative real-time polymerase chain reaction (qRT-PCR) analysis (<bold>C</bold>), immunoblotting (<bold>D</bold>). ***, <italic>p</italic> < 0.001. (<bold>E</bold>,<bold>F</bold>) SESN2 protein levels in the Oxaliplatin and DHA combination was analyzed by immunoblotting (<bold>E</bold>) and immunofluorescence (<bold>F</bold>) (Scale bar, 10 μm). (<bold>G</bold>,<bold>H</bold>) Following transfection with control small interfering RNA (siRNA) or SESN2 siRNA, cells were exposed to the Oxaliplatin and DHA combination. The mRNA (<bold>G</bold>) and protein (<bold>H</bold>) expression of LC3 and p62 were evaluated using qRT-PCR and western blotting. ***, <italic>p</italic> < 0.001.</p></caption><graphic xlink:href="cancers-11-00982-g003"></graphic></fig><fig id="cancers-11-00982-f004" orientation="portrait" position="float"><label>Figure 4</label><caption><p>Combined treatment with Oxaliplatin and DHA induces endoplasmic reticulum (ER) stress overproduction. (<bold>A</bold>,<bold>B</bold>) HCT116 cells were exposed to different doses of Oxaliplatin and DHA (<bold>A</bold>) and time periods (<bold>B</bold>). HCT116 cell lysates were analyzed with an immunoblotting assay using ER stress-related antibodies. (<bold>C</bold>) C/EBP homologous protein (CHOP) was confirmed via immunofluorescence in the Oxaliplatin and DHA combination (Scale Bar, 10 μM). (<bold>D</bold>,<bold>E</bold>) Following transfection with control siRNA or CHOP siRNA, the mRNA(<bold>D</bold>) and protein (<bold>E</bold>) levels of LC3 and p62 were detected via qRT-PCR and immunoblotting. **, <italic>p</italic> < 0.001. (<bold>F</bold>) Cells were exposed to Oxaliplatin and DHA with or without thapsigargin, and the p62 and LC3 levels were observed via western blotting.</p></caption><graphic xlink:href="cancers-11-00982-g004"></graphic></fig><fig id="cancers-11-00982-f005" orientation="portrait" position="float"><label>Figure 5</label><caption><p>CHOP regulates SESN2 activity by binding directly to the SESN2 promoter region. (<bold>A</bold>) The correlation of SESN2 expression and ER stress-related genes in CRC patients. (<bold>B</bold>) HCT116 cells were pre-treated with thapsigargin for 1 h and then exposed to the Oxaliplatin and DHA combination for 24 h. SESN2 protein expression was confirmed with western blotting. (<bold>C</bold>–<bold>F</bold>) Following transfection with control siRNA, CHOP siRNA, or SESN2 siRNA, the SESN2 and CHOP protein levels were determined using qRT-PCR (<bold>C</bold>,<bold>E</bold>) and immunoblotting (<bold>D</bold>,<bold>F</bold>). ***, <italic>p</italic> < 0.001. (<bold>G</bold>) Illustration of the three predicted CHOP binding sites (BS) and ATF BS in the SESN2 promoter. (<bold>H</bold>) Cells were treated with Oxaliplatin and DHA, and then immunoprecipitated with either IgG or CHOP.</p></caption><graphic xlink:href="cancers-11-00982-g005"></graphic></fig><fig id="cancers-11-00982-f006" orientation="portrait" position="float"><label>Figure 6</label><caption><p>Combinatorial treatment with DHA and Oxaliplatin increases CHOP expression and in vivo autophagy. (<bold>A</bold>–<bold>D</bold>) Nude mice were subcutaneously inoculated with 1 × 107 HCT116-Luc+ Cells. When tumor volume reached approximately 200 mm<sup>3</sup>, the mice were treated with EtOH, DHA (10 mg/kg), Oxaliplatin (10 mg/kg), or the combinatorial treatment of DHA and Oxaliplatin (10 mg/kg), administered 3 times a week for 2 weeks. (<bold>A</bold>) Mice were imaged using the NightOWL LB983 bioluminescence imaging (BLI) system. (<bold>B</bold>) Line graph illustrating the tumor volume (mm<sup>3</sup>). ***, <italic>p</italic> < 0.001. (<bold>C</bold>) Tumor tissues were harvested on day 14 and then imaged using a digital camera. (<bold>D</bold>) Graph illustrating body weight. **, <italic>p</italic> < 0.01. (<bold>E</bold>,<bold>F</bold>) Immunohistochemistry (IHC) showing LC3 (upper panel), CHOP (middle panel), and SESN2 (lower panel) in the tumors from xenograft at a 400× magnification. (Scale bar, 20 μm). **, <italic>p</italic> < 0.01 and ***, <italic>p</italic> < 0.001.</p></caption><graphic xlink:href="cancers-11-00982-g006"></graphic></fig><fig id="cancers-11-00982-f007" orientation="portrait" position="float"><label>Figure 7</label><caption><p>Scheme of autophagic cell death induced by the combination of Oxaliplatin and DHA.</p></caption><graphic xlink:href="cancers-11-00982-g007"></graphic></fig></floats-group></pmc><affiliations><list><country><li>Corée du Sud</li></country><region><li>Région capitale de Séoul</li></region><settlement><li>Séoul</li></settlement></list><tree><country name="Corée du Sud"><region name="Région capitale de Séoul"><name sortKey="Jeong, Soyeon" sort="Jeong, Soyeon" uniqKey="Jeong S" first="Soyeon" last="Jeong">Soyeon Jeong</name></region><name sortKey="Jeong, Yoon A" sort="Jeong, Yoon A" uniqKey="Jeong Y" first="Yoon A." last="Jeong">Yoon A. Jeong</name><name sortKey="Jo, Min Jee" sort="Jo, Min Jee" uniqKey="Jo M" first="Min Jee" last="Jo">Min Jee Jo</name><name sortKey="Kang, Sang Hee" sort="Kang, Sang Hee" uniqKey="Kang S" first="Sang Hee" last="Kang">Sang Hee Kang</name><name sortKey="Kim, Bo Ram" sort="Kim, Bo Ram" uniqKey="Kim B" first="Bo Ram" last="Kim">Bo Ram Kim</name><name sortKey="Kim, Bu Gyeom" sort="Kim, Bu Gyeom" uniqKey="Kim B" first="Bu Gyeom" last="Kim">Bu Gyeom Kim</name><name sortKey="Kim, Dae Yeong" sort="Kim, Dae Yeong" uniqKey="Kim D" first="Dae Yeong" last="Kim">Dae Yeong Kim</name><name sortKey="Kim, Jung Lim" sort="Kim, Jung Lim" uniqKey="Kim J" first="Jung Lim" last="Kim">Jung Lim Kim</name><name sortKey="Lee, Dae Hee" sort="Lee, Dae Hee" uniqKey="Lee D" first="Dae-Hee" last="Lee">Dae-Hee Lee</name><name sortKey="Lee, Dae Hee" sort="Lee, Dae Hee" uniqKey="Lee D" first="Dae-Hee" last="Lee">Dae-Hee Lee</name><name sortKey="Na, Yoo Jin" sort="Na, Yoo Jin" uniqKey="Na Y" first="Yoo Jin" last="Na">Yoo Jin Na</name><name sortKey="Oh, Sang Cheul" sort="Oh, Sang Cheul" uniqKey="Oh S" first="Sang Cheul" last="Oh">Sang Cheul Oh</name><name sortKey="Oh, Sang Cheul" sort="Oh, Sang Cheul" uniqKey="Oh S" first="Sang Cheul" last="Oh">Sang Cheul Oh</name><name sortKey="Park, Seong Hye" sort="Park, Seong Hye" uniqKey="Park S" first="Seong Hye" last="Park">Seong Hye Park</name><name sortKey="Yun, Hye Kyeong" sort="Yun, Hye Kyeong" uniqKey="Yun H" first="Hye Kyeong" last="Yun">Hye Kyeong Yun</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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