Protein disulfide isomerase inhibition synergistically enhances the efficacy of sorafenib for hepatocellular carcinoma

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dc.contributor.authorWon, Jae-Kyungko
dc.contributor.authorYu, Su Jongko
dc.contributor.authorHwang, Chae Youngko
dc.contributor.authorCho, Sung-Hwanko
dc.contributor.authorPark, Sang-Minko
dc.contributor.authorKim, Kwangsooko
dc.contributor.authorChoi, Won-Mookko
dc.contributor.authorCho, Hyekiko
dc.contributor.authorCho, Eun Juko
dc.contributor.authorLee, Jeong-Hoonko
dc.contributor.authorLee, Kyung Bunko
dc.contributor.authorKim, Yoon Junko
dc.contributor.authorSuh, Kyung-Sukko
dc.contributor.authorJang, Ja-Juneko
dc.contributor.authorKim, Chung Yongko
dc.contributor.authorYoon, Jung-Hwanko
dc.contributor.authorCho, Kwang-Hyunko
dc.date.accessioned2017-09-25T05:13:31Z-
dc.date.available2017-09-25T05:13:31Z-
dc.date.created2017-06-21-
dc.date.created2017-06-21-
dc.date.created2017-06-21-
dc.date.issued2017-09-
dc.identifier.citationHEPATOLOGY, v.66, no.3, pp.855 - 868-
dc.identifier.issn0270-9139-
dc.identifier.urihttp://hdl.handle.net/10203/226027-
dc.description.abstractSorafenib is the only approved targeted drug for hepatocellular carcinoma (HCC), but its effect on patients' survival gain is limited and varies over a wide range depending on pathogenetic conditions. Thus, enhancing the efficacy of sorafenib and finding a reliable predictive biomarker are crucial to achieve efficient control of HCCs. In this study, we utilized a systems approach by combining transcriptome analysis of the mRNA changes in HCC cell lines in response to sorafenib with network analysis to investigate the action and resistance mechanism of sorafenib. Gene list functional enrichment analysis and gene set enrichment analysis revealed that proteotoxic stress and apoptosis modules are activated in the presence of sorafenib. Further analysis of the endoplasmic reticulum stress network model, combined with in vitro experiments, showed that introducing an additional stress by treating the orally active protein disulfide isomerase (PDI) inhibitor (PACMA 31) can synergistically increase the efficacy of sorafenib in vitro and in vivo, which was confirmed using a mouse xenograft model. We also found that HCC patients with high PDI expression show resistance to sorafenib and poor clinical outcomes, compared to the low-PDI-expression group. Conclusion: These results suggest that PDI is a promising therapeutic target for enhancing the efficacy of sorafenib and can also be a biomarker for predicting sorafenib responsiveness.-
dc.languageEnglish-
dc.publisherWILEY-BLACKWELL-
dc.titleProtein disulfide isomerase inhibition synergistically enhances the efficacy of sorafenib for hepatocellular carcinoma-
dc.typeArticle-
dc.identifier.wosid000408307200017-
dc.identifier.scopusid2-s2.0-85028028086-
dc.type.rimsART-
dc.citation.volume66-
dc.citation.issue3-
dc.citation.beginningpage855-
dc.citation.endingpage868-
dc.citation.publicationnameHEPATOLOGY-
dc.identifier.doi10.1002/hep.29237-
dc.contributor.localauthorCho, Kwang-Hyun-
dc.contributor.nonIdAuthorYu, Su Jong-
dc.contributor.nonIdAuthorKim, Kwangsoo-
dc.contributor.nonIdAuthorChoi, Won-Mook-
dc.contributor.nonIdAuthorCho, Hyeki-
dc.contributor.nonIdAuthorCho, Eun Ju-
dc.contributor.nonIdAuthorLee, Jeong-Hoon-
dc.contributor.nonIdAuthorLee, Kyung Bun-
dc.contributor.nonIdAuthorKim, Yoon Jun-
dc.contributor.nonIdAuthorSuh, Kyung-Suk-
dc.contributor.nonIdAuthorJang, Ja-June-
dc.contributor.nonIdAuthorKim, Chung Yong-
dc.contributor.nonIdAuthorYoon, Jung-Hwan-
dc.description.isOpenAccessN-
dc.type.journalArticleArticle-
dc.subject.keywordPlusENDOPLASMIC-RETICULUM STRESS-
dc.subject.keywordPlusCELL-DEATH-
dc.subject.keywordPlusEXPRESSION-
dc.subject.keywordPlusRESISTANCE-
dc.subject.keywordPlusDECISIONS-
dc.subject.keywordPlusAPOPTOSIS-
dc.subject.keywordPlusTHERAPY-
dc.subject.keywordPlusHYPOXIA-
dc.subject.keywordPlusGROWTH-
dc.subject.keywordPlusCANCER-
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