Chloroquine promotes gefitinib-induced apoptosis by inhibiting protective autophagy in cutaneous squamous cell carcinoma
Identifieur interne : 000706 ( Pmc/Curation ); précédent : 000705; suivant : 000707Chloroquine promotes gefitinib-induced apoptosis by inhibiting protective autophagy in cutaneous squamous cell carcinoma
Auteurs : Chengshan Ou [République populaire de Chine] ; Hongxia Liu [République populaire de Chine] ; Zhenhua Ding [République populaire de Chine] ; Liang Zhou [République populaire de Chine]Source :
- Molecular Medicine Reports [ 1791-2997 ] ; 2019.
Abstract
Aberrant expression of the epidermal growth factor receptor (EGFR) plays vital roles in tumor development and progression. In the present study, ultraviolet irradiation induced the upregulation of EGFR in skin-derived keratinocytes, which may contribute to the development of cutaneous squamous cell carcinoma (CSCC). This was supported by the high expression of EGFR in CSCC clinical samples. Treating A431 CSCC cells with gefitinib, a tyrosine kinase inhibitor, activated the intrinsic mitochondrial apoptotic pathway while inducing protective autophagy. Combined application of chloroquine with gefitinib enhanced the treatment efficacy of gefitinib against CSCC by inhibiting autophagic flux. These findings demonstrated that autophagy inhibition may be an effective strategy for enhancing the sensitivity of EGFR-expressing cells to tyrosine kinase inhibitor treatment. Manipulating pro-survival autophagy by the combined application of chloroquine with gefitinib is a promising approach for improving the efficacy of EGFR inhibitors in cancer treatment. This may contribute to novel EGFR-targeted therapeutic strategies in the near future.
Url:
DOI: 10.3892/mmr.2019.10734
PubMed: 31638204
PubMed Central: 6854599
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China</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>Department of Radiation Medicine, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, Guangdong 510515</wicri:regionArea></affiliation></author><author><name sortKey="Liu, Hongxia" sort="Liu, Hongxia" uniqKey="Liu H" first="Hongxia" last="Liu">Hongxia Liu</name><affiliation wicri:level="1"><nlm:aff id="af1-mmr-20-06-4855">Department of Radiation Medicine, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>Department of Radiation Medicine, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, Guangdong 510515</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="af2-mmr-20-06-4855">Institute of Radiation Medicine, Fudan University, Shanghai 200032, P.R. China</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>Institute of Radiation Medicine, Fudan University, Shanghai 200032</wicri:regionArea></affiliation></author><author><name sortKey="Ding, Zhenhua" sort="Ding, Zhenhua" uniqKey="Ding Z" first="Zhenhua" last="Ding">Zhenhua Ding</name><affiliation wicri:level="1"><nlm:aff id="af1-mmr-20-06-4855">Department of Radiation Medicine, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, Guangdong 510515, P.R. 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China</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>Department of Toxicology, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, Guangdong 510515</wicri:regionArea></affiliation></author></analytic><series><title level="j">Molecular Medicine Reports</title><idno type="ISSN">1791-2997</idno><idno type="eISSN">1791-3004</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>Aberrant expression of the epidermal growth factor receptor (EGFR) plays vital roles in tumor development and progression. In the present study, ultraviolet irradiation induced the upregulation of EGFR in skin-derived keratinocytes, which may contribute to the development of cutaneous squamous cell carcinoma (CSCC). This was supported by the high expression of EGFR in CSCC clinical samples. Treating A431 CSCC cells with gefitinib, a tyrosine kinase inhibitor, activated the intrinsic mitochondrial apoptotic pathway while inducing protective autophagy. Combined application of chloroquine with gefitinib enhanced the treatment efficacy of gefitinib against CSCC by inhibiting autophagic flux. These findings demonstrated that autophagy inhibition may be an effective strategy for enhancing the sensitivity of EGFR-expressing cells to tyrosine kinase inhibitor treatment. Manipulating pro-survival autophagy by the combined application of chloroquine with gefitinib is a promising approach for improving the efficacy of EGFR inhibitors in cancer treatment. 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Mol Med Rep</journal-id><journal-id journal-id-type="iso-abbrev">Mol Med Rep</journal-id><journal-title-group><journal-title>Molecular Medicine Reports</journal-title></journal-title-group><issn pub-type="ppub">1791-2997</issn><issn pub-type="epub">1791-3004</issn><publisher><publisher-name>D.A. Spandidos</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">31638204</article-id><article-id pub-id-type="pmc">6854599</article-id><article-id pub-id-type="doi">10.3892/mmr.2019.10734</article-id><article-id pub-id-type="publisher-id">mmr-20-06-4855</article-id><article-categories><subj-group subj-group-type="heading"><subject>Articles</subject></subj-group></article-categories><title-group><article-title>Chloroquine promotes gefitinib-induced apoptosis by inhibiting protective autophagy in cutaneous squamous cell carcinoma</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Ou</surname><given-names>Chengshan</given-names></name><xref ref-type="aff" rid="af1-mmr-20-06-4855">1</xref><xref rid="fn1-mmr-20-06-4855" ref-type="author-notes">*</xref></contrib><contrib contrib-type="author"><name><surname>Liu</surname><given-names>Hongxia</given-names></name><xref ref-type="aff" rid="af1-mmr-20-06-4855">1</xref><xref ref-type="aff" rid="af2-mmr-20-06-4855">2</xref><xref rid="fn1-mmr-20-06-4855" ref-type="author-notes">*</xref></contrib><contrib contrib-type="author"><name><surname>Ding</surname><given-names>Zhenhua</given-names></name><xref ref-type="aff" rid="af1-mmr-20-06-4855">1</xref></contrib><contrib contrib-type="author"><name><surname>Zhou</surname><given-names>Liang</given-names></name><xref ref-type="aff" rid="af3-mmr-20-06-4855">3</xref><xref rid="c1-mmr-20-06-4855" ref-type="corresp"></xref></contrib></contrib-group><aff id="af1-mmr-20-06-4855"><label>1</label>Department of Radiation Medicine, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China</aff><aff id="af2-mmr-20-06-4855"><label>2</label>Institute of Radiation Medicine, Fudan University, Shanghai 200032, P.R. China</aff><aff id="af3-mmr-20-06-4855"><label>3</label>Department of Toxicology, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China</aff><author-notes><corresp id="c1-mmr-20-06-4855"><italic>Correspondence to</italic>: Professor Liang Zhou, Department of Toxicology, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, 1838 Northern Guangzhou Avenue, Guangzhou, Guangdong 510515, P.R. China, E-mail: <email>zhzliang@smu.edu.cn</email></corresp><fn id="fn1-mmr-20-06-4855"><label>*</label><p>Contributed equally</p></fn></author-notes><pub-date pub-type="ppub"><month>12</month><year>2019</year></pub-date><pub-date pub-type="epub"><day>09</day><month>10</month><year>2019</year></pub-date><pub-date pub-type="pmc-release"><day>09</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>20</volume><issue>6</issue><fpage>4855</fpage><lpage>4866</lpage><history><date date-type="received"><day>08</day><month>11</month><year>2018</year></date><date date-type="accepted"><day>26</day><month>7</month><year>2019</year></date></history><permissions><copyright-statement>Copyright: © Ou 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>Aberrant expression of the epidermal growth factor receptor (EGFR) plays vital roles in tumor development and progression. In the present study, ultraviolet irradiation induced the upregulation of EGFR in skin-derived keratinocytes, which may contribute to the development of cutaneous squamous cell carcinoma (CSCC). This was supported by the high expression of EGFR in CSCC clinical samples. Treating A431 CSCC cells with gefitinib, a tyrosine kinase inhibitor, activated the intrinsic mitochondrial apoptotic pathway while inducing protective autophagy. Combined application of chloroquine with gefitinib enhanced the treatment efficacy of gefitinib against CSCC by inhibiting autophagic flux. These findings demonstrated that autophagy inhibition may be an effective strategy for enhancing the sensitivity of EGFR-expressing cells to tyrosine kinase inhibitor treatment. Manipulating pro-survival autophagy by the combined application of chloroquine with gefitinib is a promising approach for improving the efficacy of EGFR inhibitors in cancer treatment. This may contribute to novel EGFR-targeted therapeutic strategies in the near future.</p></abstract><kwd-group><kwd>gefitinib</kwd><kwd>epidermal growth factor receptor</kwd><kwd>chloroquine</kwd><kwd>apoptosis</kwd><kwd>autophagy</kwd></kwd-group></article-meta></front><floats-group><fig id="f1-mmr-20-06-4855" orientation="portrait" position="float"><label>Figure 1.</label><caption><p>Expression of EGFR in CSCC. (A) HaCaT cells were exposed to UVB (30 mJ/cm<sup>2</sup>) irradiation at indicated time-points and then the expression levels of EGFR were detected using western blot analysis. * P<0.05, ** P<0.01 vs. NC. GAPDH served as the loading control. (B) EGFR and GAPDH in human HaCaT and A431 cell lines were detected by western blotting. ** P<0.01 vs. HaCaT (C) IHC detection of EGFR expression in human normal skin and CSCC tissues (n=20) (scale bar, 100 µm). ** P<0.01 (D) A431 cells were treated with gefitinib (100 µM) for 9 or 12 h, and p-EGFR EGFR and GAPDH were immunoblotted using appropriate antibodies. * P<0.05 vs. NC-9 h. EGFR, epidermal growth factor receptor; CSCC, cutaneous squamous cell carcinoma; IHC, immunohistochemistry.</p></caption><graphic xlink:href="MMR-20-06-4855-g00"></graphic></fig><fig id="f2-mmr-20-06-4855" orientation="portrait" position="float"><label>Figure 2.</label><caption><p>Gefitinib treatment suppresses the proliferation, mobility and invasiveness of CSCC cells. (A) The proliferation ability of A431 cells treated with gefitinib (100 µM) was assessed by CCK-8 assays. (B) The representative images of crystal violet-stained cell colonies in A431 cells treated with gefitinib (10 or 20 µM) are presented (scale bar, 50 µm). (C) Colony formation ability of A431 cells following treatment with gefitinib (100 µM) or with DMSO as a control for different time-points. (D) The effect of gefitinib (50 or 100 µM) on A431 cell mobility for indicated time-points is presented (scale bar, 100 µm). (E) Invasive and migratory capacities of A431 cells treated with gefitinib (10, 20, or 50 µM) or with DMSO as a control were detected by Matrigel-coated or Matrigel-non-coated Transwell assays, respectively (scale bar, 50 µm). (F) qPCR analysis of the expression of N-cadherin and vimentin. ** P<0.01. CSCC, cutaneous squamous cell carcinoma.</p></caption><graphic xlink:href="MMR-20-06-4855-g01"></graphic></fig><fig id="f3-mmr-20-06-4855" orientation="portrait" position="float"><label>Figure 3.</label><caption><p>Gefitinib treatment can induce apoptosis and autophagy in CSCC cells. (A) A431 cells were treated with indicated concentrations of gefitinib for 12 h and then the total cell apoptosis rate was analyzed by flow cytometric analysis. CSCC, cutaneous squamous cell carcinoma. Gefitinib treatment can induce apoptosis and autophagy in CSCC cells. (B) A431 cells were treated with gefitinib (100 µM) or with DMSO as a control and then the total cell apoptosis rate was assessed at various time-points by flow cytometric analysis. **P<0.01. CSCC, cutaneous squamous cell carcinoma. Gefitinib treatment can induce apoptosis and autophagy in CSCC cells. (C) A431 cells were incubated with gefitinib (100 µM) for 12 h, and then cellular apoptosis was observed using electron microscopy. Chromosomal condensation and apoptotic bodies were highlighted by arrows. (D) Cellular autophagy was detected by electron microscopy. Autophagic vacuoles containing organelle remnants were highlighted by arrows. (E) The autophagy in A431 cells following gefitinib (scale bar, 50 µM) treatment was analyzed by AO staining. (F) A431 cells were treated with gefitinib (100 µM) or with DMSO as a control and then apoptosis and autophagy were monitored at various time-points by detecting caspase-3, caspase-9, and the total accumulation of LC3-II using western blotting analysis. GAPDH served as the loading control. *P<0.05 vs. NC-3 h. (G) LC3-II expression detected after gefitinib and 3-methyladenine (3-MA) treatments. *P<0.05 vs. NC. CSCC, cutaneous squamous cell carcinoma.</p></caption><graphic xlink:href="MMR-20-06-4855-g02"></graphic><graphic xlink:href="MMR-20-06-4855-g03"></graphic><graphic xlink:href="MMR-20-06-4855-g04"></graphic></fig><fig id="f4-mmr-20-06-4855" orientation="portrait" position="float"><label>Figure 4.</label><caption><p>Autophagy inhibition by chloroquine attenuates CSCC cell proliferation and promotes cell apoptosis. (A) A431 cells were treated with indicated concentrations of gefitinib and chloroquine or with DMSO and PBS as a control for 12 h and then the proliferation ability was detected by CCK-8 assays. (B) A431 cells were treated with indicated treatments for 12 h and then the invasive and migratory capacities were detected by Matrigel-coated or Matrigel-non-coated Transwell assays, respectively. Scale bar, 100 µm. (C) Total apoptosis rate of 431 cells following indicated treatments for 12 h was analyzed by flow cytometric analysis. GAPDH served as the loading control. CSCC, cutaneous squamous cell carcinoma. Autophagy inhibition by chloroquine attenuates CSCC cell proliferation and promotes cell apoptosis. (D) Total apoptosis rate of 431 cells following indicated treatments for 12 h was analyzed by flow cytometric analysis. (E) A431 cells were treated with indicated treatments for 12 h and then apoptosis and autophagy were monitored by detecting caspase-3, caspase-9, LC3-II, and SQSTM1 using western blotting analysis. GAPDH served as the loading control. *P<0.05 vs. NC. CSCC, cutaneous squamous cell carcinoma.</p></caption><graphic xlink:href="MMR-20-06-4855-g05"></graphic><graphic xlink:href="MMR-20-06-4855-g06"></graphic></fig></floats-group></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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