Autophagic Inhibition via Lysosomal Integrity Dysfunction Leads to Antitumor Activity in Glioma Treatment

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dc.contributor.authorHwang, Hui-Yunko
dc.contributor.authorCho, Yoon Sunko
dc.contributor.authorKim, Jin Youngko
dc.contributor.authorYun, Ki Nako
dc.contributor.authorYoo, Jong Shinko
dc.contributor.authorLee, Eunhyeongko
dc.contributor.authorKim, Injuneko
dc.contributor.authorKwon, Ho Jeongko
dc.date.accessioned2020-06-10T09:20:23Z-
dc.date.available2020-06-10T09:20:23Z-
dc.date.created2020-06-08-
dc.date.issued2020-03-
dc.identifier.citationCANCERS, v.12, no.3-
dc.identifier.issn2072-6694-
dc.identifier.urihttp://hdl.handle.net/10203/274600-
dc.description.abstractManipulating autophagy is a promising strategy for treating cancer as several autophagy inhibitors are shown to induce autophagic cell death. One of these, autophagonizer (APZ), induces apoptosis-independent cell death by binding an unknown target via an unknown mechanism. To identify APZ targets, we used a label-free drug affinity responsive target stability (DARTS) approach with a liquid chromatography/tandem mass spectrometry (LC-MS/MS) readout. Of 35 protein interactors, we identified Hsp70 as a key target protein of unmodified APZ in autophagy. Either APZ treatment or Hsp70 inhibition attenuates integrity of lysosomes, which leads to autophagic cell death exhibiting an excellent synergism with a clinical drug, temozolomide, in vitro, in vivo, and orthotropic glioma xenograft model. These findings demonstrate the potential of APZ to induce autophagic cell death and its development to combinational chemotherapeutic agent for glioma treatment. Collectively, our study demonstrated that APZ, a new autophagy inhibitor, can be used as a potent antitumor drug candidate to get over unassailable glioma and revealed a novel function of Hsp70 in lysosomal integrity regulation of autophagy.-
dc.languageEnglish-
dc.publisherMDPI-
dc.titleAutophagic Inhibition via Lysosomal Integrity Dysfunction Leads to Antitumor Activity in Glioma Treatment-
dc.typeArticle-
dc.identifier.wosid000530232300019-
dc.identifier.scopusid2-s2.0-85081075680-
dc.type.rimsART-
dc.citation.volume12-
dc.citation.issue3-
dc.citation.publicationnameCANCERS-
dc.identifier.doi10.3390/cancers12030543-
dc.contributor.localauthorKim, Injune-
dc.contributor.nonIdAuthorHwang, Hui-Yun-
dc.contributor.nonIdAuthorCho, Yoon Sun-
dc.contributor.nonIdAuthorKim, Jin Young-
dc.contributor.nonIdAuthorYun, Ki Na-
dc.contributor.nonIdAuthorYoo, Jong Shin-
dc.contributor.nonIdAuthorKwon, Ho Jeong-
dc.description.isOpenAccessY-
dc.type.journalArticleArticle-
dc.subject.keywordAuthorautophagy-
dc.subject.keywordAuthorautophagonizer-
dc.subject.keywordAuthortarget identification of label-free compound-
dc.subject.keywordAuthortarget validation-
dc.subject.keywordAuthorautophagic flux-
dc.subject.keywordAuthorautophagy inhibition-
dc.subject.keywordAuthorlysosomal integrity function of Hsp70-
dc.subject.keywordPlusSMALL-MOLECULE INHIBITOR-
dc.subject.keywordPlusCELL-DEATH-
dc.subject.keywordPlusATPASE-
dc.subject.keywordPlusFLUX-
dc.subject.keywordPlusAPOPTOSIS-
dc.subject.keywordPlusHSP70-
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