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Article: Induction of oxidative stress through inhibition of thioredoxin reductase 1 is an effective therapeutic approach for hepatocellular carcinoma

TitleInduction of oxidative stress through inhibition of thioredoxin reductase 1 is an effective therapeutic approach for hepatocellular carcinoma
Authors
Issue Date2019
PublisherJohn Wiley & Sons, Inc. The Journal's web site is located at http://www.hepatology.org/
Citation
Hepatology, 2019, v. 69 n. 4, p. 1768-1786 How to Cite?
AbstractHepatocellular carcinoma (HCC) is one of the most prevalent and lethal cancers worldwide which lacks effective treatment. Cancer cells experience high levels of oxidative stress due to increased generation of reactive oxygen species (ROS). Increased antioxidant‐producing capacity is therefore found in cancer cells to counteract oxidative stress. The thioredoxin system is a ubiquitous mammalian antioxidant system which scavenges ROS, and we demonstrate that it is vital for HCC growth as it maintains intracellular reduction‐oxidation (redox) homeostasis. Transcriptome sequencing in human HCC samples revealed significant overexpression of thioredoxin reductase 1 (TXNRD1), the cytosolic subunit and key enzyme of the thioredoxin system, with significant correlations to poorer clinicopathological features and patient survival. Driven by the transcriptional activation of nuclear factor (erythroid‐derived 2)–like 2, the master protector against oxidative stress, TXNRD1 counteracts intracellular ROS produced in human HCC. Inhibition of TXNRD1 through genetic inhibition hindered the proliferation of HCC cells and induced apoptosis in vitro. Administration of the pharmacological TXNRD1 inhibitor auranofin (AUR) effectively suppressed the growth of HCC tumors induced using the hydrodynamic tail vein injection and orthotopic implantation models in vivo. Furthermore, AUR sensitized HCC cells toward the conventional therapeutic sorafenib. Conclusion: Our study highlights the reliance of HCC cells on antioxidants for redox homeostasis and growth advantage; targeting TXNRD1 resulted in dramatic accumulation of ROS, which was found to be an effective approach for the suppression of HCC tumor growth.
Persistent Identifierhttp://hdl.handle.net/10722/271295
ISSN
2017 Impact Factor: 14.079
2015 SCImago Journal Rankings: 4.752

 

DC FieldValueLanguage
dc.contributor.authorLee, D-
dc.contributor.authorXU, IMJ-
dc.contributor.authorCHIU, DKC-
dc.contributor.authorLeibold, J-
dc.contributor.authorTse, APW-
dc.contributor.authorBao, MHR-
dc.contributor.authorYuen, VWH-
dc.contributor.authorChan, CYK-
dc.contributor.authorLAI, RKH-
dc.contributor.authorChin, DWC-
dc.contributor.authorChan, DFF-
dc.contributor.authorCheung, TT-
dc.contributor.authorChok, SH-
dc.contributor.authorWong, CM-
dc.contributor.authorLowe, SW-
dc.contributor.authorNg, IOL-
dc.contributor.authorWong, CCL-
dc.date.accessioned2019-06-24T01:07:07Z-
dc.date.available2019-06-24T01:07:07Z-
dc.date.issued2019-
dc.identifier.citationHepatology, 2019, v. 69 n. 4, p. 1768-1786-
dc.identifier.issn0270-9139-
dc.identifier.urihttp://hdl.handle.net/10722/271295-
dc.description.abstractHepatocellular carcinoma (HCC) is one of the most prevalent and lethal cancers worldwide which lacks effective treatment. Cancer cells experience high levels of oxidative stress due to increased generation of reactive oxygen species (ROS). Increased antioxidant‐producing capacity is therefore found in cancer cells to counteract oxidative stress. The thioredoxin system is a ubiquitous mammalian antioxidant system which scavenges ROS, and we demonstrate that it is vital for HCC growth as it maintains intracellular reduction‐oxidation (redox) homeostasis. Transcriptome sequencing in human HCC samples revealed significant overexpression of thioredoxin reductase 1 (TXNRD1), the cytosolic subunit and key enzyme of the thioredoxin system, with significant correlations to poorer clinicopathological features and patient survival. Driven by the transcriptional activation of nuclear factor (erythroid‐derived 2)–like 2, the master protector against oxidative stress, TXNRD1 counteracts intracellular ROS produced in human HCC. Inhibition of TXNRD1 through genetic inhibition hindered the proliferation of HCC cells and induced apoptosis in vitro. Administration of the pharmacological TXNRD1 inhibitor auranofin (AUR) effectively suppressed the growth of HCC tumors induced using the hydrodynamic tail vein injection and orthotopic implantation models in vivo. Furthermore, AUR sensitized HCC cells toward the conventional therapeutic sorafenib. Conclusion: Our study highlights the reliance of HCC cells on antioxidants for redox homeostasis and growth advantage; targeting TXNRD1 resulted in dramatic accumulation of ROS, which was found to be an effective approach for the suppression of HCC tumor growth.-
dc.languageeng-
dc.publisherJohn Wiley & Sons, Inc. The Journal's web site is located at http://www.hepatology.org/-
dc.relation.ispartofHepatology-
dc.rightsThis is the peer reviewed version of the following article: [FULL CITE], which has been published in final form at [Link to final article using the DOI]. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions.-
dc.subject.meshanimal experiment-
dc.subject.meshanimal model-
dc.subject.meshapoptosis-
dc.subject.meshcell proliferation-
dc.subject.meshcontrolled study-
dc.titleInduction of oxidative stress through inhibition of thioredoxin reductase 1 is an effective therapeutic approach for hepatocellular carcinoma-
dc.typeArticle-
dc.identifier.emailTse, APW: akipwtse@hku.hk-
dc.identifier.emailYuen, VWH: whyvin@hku.hk-
dc.identifier.emailChan, CYK: ykchanaa@hku.hk-
dc.identifier.emailChin, DWC: doncwc01@hku.hk-
dc.identifier.emailCheung, TT: cheung68@hku.hk-
dc.identifier.emailChok, SH: chok6275@hku.hk-
dc.identifier.emailWong, CM: jcmwong@hku.hk-
dc.identifier.emailNg, IOL: iolng@hku.hk-
dc.identifier.emailWong, CCL: carmencl@pathology.hku.hk-
dc.identifier.authorityCheung, TT=rp02129-
dc.identifier.authorityChok, SH=rp02110-
dc.identifier.authorityWong, CM=rp00231-
dc.identifier.authorityNg, IOL=rp00335-
dc.identifier.authorityWong, CCL=rp01602-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1002/hep.30467-
dc.identifier.pmid30561826-
dc.identifier.scopuseid_2-s2.0-85063142219-
dc.identifier.hkuros297993-
dc.identifier.volume69-
dc.identifier.issue4-
dc.identifier.spage1768-
dc.identifier.epage1786-
dc.publisher.placeUnited States-

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