Claudin-2 binding peptides, VPDSM and DSMKF, down-regulate claudin-2 expression and anticancer resistance in human lung adenocarcinoma A549 cells.
Identifieur interne : 000185 ( Main/Exploration ); précédent : 000184; suivant : 000186Claudin-2 binding peptides, VPDSM and DSMKF, down-regulate claudin-2 expression and anticancer resistance in human lung adenocarcinoma A549 cells.
Auteurs : Haruka Nasako [Japon] ; Risa Akizuki [Japon] ; Yui Takashina [Japon] ; Yoshinobu Ishikawa [Japon] ; Takehiro Shinoda [Japon] ; Mikako Shirouzu [Japon] ; Tomohiro Asai [Japon] ; Toshiyuki Matsunaga [Japon] ; Satoshi Endo [Japon] ; Akira Ikari [Japon]Source :
- Biochimica et biophysica acta. Molecular cell research [ 1879-2596 ] ; 2020.
Abstract
Claudin-2 (CLDN2), a tight junctional protein, is involved in the chemoresistance in spheroid culture models of human lung adenocarcinoma A549 cells. However, there is no chemical which can improve the sensitivity to anticancer drugs. So far, we reported that DFYSP, a short peptide which mimics the second extracellular loop (ECL2) of CLDN2, decreases CLDN2 expression in A549 cells, but the concentration is relatively high. Here, we found that the effects of VPDSM and DSMKF are stronger than that of DFYSP. Both VPDSM and DSMKF decreased the protein levels of CLDN2 without affecting the mRNA levels of CLDN2. The peptide-induced decrease in CLDN2 expression was suppressed by monodansylcadaverine (MDC), a clathrin-dependent endocytosis (CDE) inhibitor, and chloroquine, a lysosome inhibitor. CLDN2 was colocalized with ZO-1, an adapter protein, in tight junctions (TJs) under control conditions, whereas it disappeared from the TJs in the peptide-treated cells. Quartz crystal microbalance assay showed that both peptides can bind to recombinant CLDN2 protein. Both peptides increased permeability to paracellular transport marker lucifer yellow. In three-dimensional spheroid culture models, both peptides enhanced the sensitivity to doxorubicin, a cytotoxic anticancer drug, which was inhibited by MDC. We suggest that VPDSM and DSMKF enhance the chemosensitivity to anticancer drugs in aggregated adenocarcinoma cells mediated by the CDE pathway and lysosomal degradation of CLDN2 in lung adenocarcinoma cells. VPDSM and DSMKF, which mimic the ECL2 of CLDN2, may become novel adjuvant therapeutic drugs for lung adenocarcinoma.
DOI: 10.1016/j.bbamcr.2019.118642
PubMed: 31923533
Affiliations:
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Gifu 501-1196</wicri:regionArea><wicri:noRegion>Gifu 501-1196</wicri:noRegion></affiliation></author><author><name sortKey="Akizuki, Risa" sort="Akizuki, Risa" uniqKey="Akizuki R" first="Risa" last="Akizuki">Risa Akizuki</name><affiliation wicri:level="1"><nlm:affiliation>Laboratory of Biochemistry, Department of Biopharmaceutical Sciences, Gifu Pharmaceutical University, Gifu 501-1196, Japan.</nlm:affiliation><country xml:lang="fr">Japon</country><wicri:regionArea>Laboratory of Biochemistry, Department of Biopharmaceutical Sciences, Gifu Pharmaceutical University, Gifu 501-1196</wicri:regionArea><wicri:noRegion>Gifu 501-1196</wicri:noRegion></affiliation></author><author><name sortKey="Takashina, Yui" sort="Takashina, Yui" uniqKey="Takashina Y" first="Yui" last="Takashina">Yui Takashina</name><affiliation wicri:level="1"><nlm:affiliation>Laboratory of Biochemistry, Department of Biopharmaceutical Sciences, Gifu Pharmaceutical University, Gifu 501-1196, Japan.</nlm:affiliation><country xml:lang="fr">Japon</country><wicri:regionArea>Laboratory of Biochemistry, Department of Biopharmaceutical Sciences, Gifu Pharmaceutical University, Gifu 501-1196</wicri:regionArea><wicri:noRegion>Gifu 501-1196</wicri:noRegion></affiliation></author><author><name sortKey="Ishikawa, Yoshinobu" sort="Ishikawa, Yoshinobu" uniqKey="Ishikawa Y" first="Yoshinobu" last="Ishikawa">Yoshinobu Ishikawa</name><affiliation wicri:level="1"><nlm:affiliation>Department of Physical Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka 422-8526, Japan.</nlm:affiliation><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Physical Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka 422-8526</wicri:regionArea><wicri:noRegion>Shizuoka 422-8526</wicri:noRegion></affiliation></author><author><name sortKey="Shinoda, Takehiro" sort="Shinoda, Takehiro" uniqKey="Shinoda T" first="Takehiro" last="Shinoda">Takehiro Shinoda</name><affiliation wicri:level="1"><nlm:affiliation>Laboratory for Protein Functional and Structural Biology, RIKEN Center for Biosystems Dynamics Research, Yokohama 230-0045, Japan.</nlm:affiliation><country xml:lang="fr">Japon</country><wicri:regionArea>Laboratory for Protein Functional and Structural Biology, RIKEN Center for Biosystems Dynamics Research, Yokohama 230-0045</wicri:regionArea><wicri:noRegion>Yokohama 230-0045</wicri:noRegion></affiliation></author><author><name sortKey="Shirouzu, Mikako" sort="Shirouzu, Mikako" uniqKey="Shirouzu M" first="Mikako" last="Shirouzu">Mikako Shirouzu</name><affiliation wicri:level="1"><nlm:affiliation>Laboratory for Protein Functional and Structural Biology, RIKEN Center for Biosystems Dynamics Research, Yokohama 230-0045, Japan.</nlm:affiliation><country xml:lang="fr">Japon</country><wicri:regionArea>Laboratory for Protein Functional and Structural Biology, RIKEN Center for Biosystems Dynamics Research, Yokohama 230-0045</wicri:regionArea><wicri:noRegion>Yokohama 230-0045</wicri:noRegion></affiliation></author><author><name sortKey="Asai, Tomohiro" sort="Asai, Tomohiro" uniqKey="Asai T" first="Tomohiro" last="Asai">Tomohiro Asai</name><affiliation wicri:level="1"><nlm:affiliation>Department of Medical Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka 422-8526, Japan.</nlm:affiliation><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Medical Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka 422-8526</wicri:regionArea><wicri:noRegion>Shizuoka 422-8526</wicri:noRegion></affiliation></author><author><name sortKey="Matsunaga, Toshiyuki" sort="Matsunaga, Toshiyuki" uniqKey="Matsunaga T" first="Toshiyuki" last="Matsunaga">Toshiyuki Matsunaga</name><affiliation wicri:level="1"><nlm:affiliation>Education Center of Green Pharmaceutical Sciences, Gifu Pharmaceutical University, Gifu 502-8585, Japan.</nlm:affiliation><country xml:lang="fr">Japon</country><wicri:regionArea>Education Center of Green Pharmaceutical Sciences, Gifu Pharmaceutical University, Gifu 502-8585</wicri:regionArea><wicri:noRegion>Gifu 502-8585</wicri:noRegion></affiliation></author><author><name sortKey="Endo, Satoshi" sort="Endo, Satoshi" uniqKey="Endo S" first="Satoshi" last="Endo">Satoshi Endo</name><affiliation wicri:level="1"><nlm:affiliation>Laboratory of Biochemistry, Department of Biopharmaceutical Sciences, Gifu Pharmaceutical University, Gifu 501-1196, Japan.</nlm:affiliation><country xml:lang="fr">Japon</country><wicri:regionArea>Laboratory of Biochemistry, Department of Biopharmaceutical Sciences, Gifu Pharmaceutical University, Gifu 501-1196</wicri:regionArea><wicri:noRegion>Gifu 501-1196</wicri:noRegion></affiliation></author><author><name sortKey="Ikari, Akira" sort="Ikari, Akira" uniqKey="Ikari A" first="Akira" last="Ikari">Akira Ikari</name><affiliation wicri:level="1"><nlm:affiliation>Laboratory of Biochemistry, Department of Biopharmaceutical Sciences, Gifu Pharmaceutical University, Gifu 501-1196, Japan. Electronic address: ikari@gifu-pu.ac.jp.</nlm:affiliation><country xml:lang="fr">Japon</country><wicri:regionArea>Laboratory of Biochemistry, Department of Biopharmaceutical Sciences, Gifu Pharmaceutical University, Gifu 501-1196</wicri:regionArea><wicri:noRegion>Gifu 501-1196</wicri:noRegion></affiliation></author></analytic><series><title level="j">Biochimica et biophysica acta. Molecular cell research</title><idno type="eISSN">1879-2596</idno><imprint><date when="2020" type="published">2020</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Claudin-2 (CLDN2), a tight junctional protein, is involved in the chemoresistance in spheroid culture models of human lung adenocarcinoma A549 cells. However, there is no chemical which can improve the sensitivity to anticancer drugs. So far, we reported that DFYSP, a short peptide which mimics the second extracellular loop (ECL2) of CLDN2, decreases CLDN2 expression in A549 cells, but the concentration is relatively high. Here, we found that the effects of VPDSM and DSMKF are stronger than that of DFYSP. Both VPDSM and DSMKF decreased the protein levels of CLDN2 without affecting the mRNA levels of CLDN2. The peptide-induced decrease in CLDN2 expression was suppressed by monodansylcadaverine (MDC), a clathrin-dependent endocytosis (CDE) inhibitor, and chloroquine, a lysosome inhibitor. CLDN2 was colocalized with ZO-1, an adapter protein, in tight junctions (TJs) under control conditions, whereas it disappeared from the TJs in the peptide-treated cells. Quartz crystal microbalance assay showed that both peptides can bind to recombinant CLDN2 protein. Both peptides increased permeability to paracellular transport marker lucifer yellow. In three-dimensional spheroid culture models, both peptides enhanced the sensitivity to doxorubicin, a cytotoxic anticancer drug, which was inhibited by MDC. We suggest that VPDSM and DSMKF enhance the chemosensitivity to anticancer drugs in aggregated adenocarcinoma cells mediated by the CDE pathway and lysosomal degradation of CLDN2 in lung adenocarcinoma cells. VPDSM and DSMKF, which mimic the ECL2 of CLDN2, may become novel adjuvant therapeutic drugs for lung adenocarcinoma.</div></front></TEI><affiliations><list><country><li>Japon</li></country></list><tree><country name="Japon"><noRegion><name sortKey="Nasako, Haruka" sort="Nasako, Haruka" uniqKey="Nasako H" first="Haruka" last="Nasako">Haruka Nasako</name></noRegion><name sortKey="Akizuki, Risa" sort="Akizuki, Risa" uniqKey="Akizuki R" first="Risa" last="Akizuki">Risa Akizuki</name><name sortKey="Asai, Tomohiro" sort="Asai, Tomohiro" uniqKey="Asai T" first="Tomohiro" last="Asai">Tomohiro Asai</name><name sortKey="Endo, Satoshi" sort="Endo, Satoshi" uniqKey="Endo S" first="Satoshi" last="Endo">Satoshi Endo</name><name sortKey="Ikari, Akira" sort="Ikari, Akira" uniqKey="Ikari A" first="Akira" last="Ikari">Akira Ikari</name><name sortKey="Ishikawa, Yoshinobu" sort="Ishikawa, Yoshinobu" uniqKey="Ishikawa Y" first="Yoshinobu" last="Ishikawa">Yoshinobu Ishikawa</name><name sortKey="Matsunaga, Toshiyuki" sort="Matsunaga, Toshiyuki" uniqKey="Matsunaga T" first="Toshiyuki" last="Matsunaga">Toshiyuki Matsunaga</name><name sortKey="Shinoda, Takehiro" sort="Shinoda, Takehiro" uniqKey="Shinoda T" first="Takehiro" last="Shinoda">Takehiro Shinoda</name><name sortKey="Shirouzu, Mikako" sort="Shirouzu, Mikako" uniqKey="Shirouzu M" first="Mikako" last="Shirouzu">Mikako Shirouzu</name><name sortKey="Takashina, Yui" sort="Takashina, Yui" uniqKey="Takashina Y" first="Yui" last="Takashina">Yui Takashina</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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