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Article: The PERK/eIF2α signaling pathway of Unfolded Protein Response is essential for N-(4-hydroxyphenyl)retinamide (4HPR)-induced cytotoxicity in cancer cells

TitleThe PERK/eIF2α signaling pathway of Unfolded Protein Response is essential for N-(4-hydroxyphenyl)retinamide (4HPR)-induced cytotoxicity in cancer cells
Authors
Issue Date2008
PublisherAcademic Press. The Journal's web site is located at http://www.elsevier.com/locate/yexcr
Citation
Experimental Cell Research, 2008, v. 314 n. 8, p. 1667-1682 How to Cite?
AbstractN-(4-hydroxyphenyl)retinamide (4HPR) is a synthetic retinoid that has been tested in clinical trials as a cancer chemopreventive drug. 4HPR is cytotoxic to cancer cells but the underlying molecular mechanisms are at present only partially understood. Here we demonstrate that in the human cervical cancer cell line HeLa and the human leukemia cell line HL-60, 4HPR caused rapid, Reactive Oxygen Species (ROS)-dependent activation of the Unfolded Protein Response (UPR). In HeLa cells, 4HPR was shown to induce cell death and activation of procaspases. These effects of 4HPR could be abolished by the over-expression of dominant negative mutants of PERK or eIF2α. HeLa cells incubated with 4HPR were found to form autophagosomes that were also mediated by the PERK/eIF2α pathway. While 4HPR-induced cell death could be significantly prevented by the presence of specific caspase inhibitors, 3-methyladenine (3-MA) that inhibits autophagosome formation enhanced 4HPR-induced cell death. Examination of individual 4HPR-treated HeLa cells revealed that those without the development of autophagosomes hence exhibiting an incomplete UPR were caspase-active and were not viable, while those with autophagosomes were caspase-inactive and retained cell viability. Our data suggest that the PERK/eIF2α pathway is essential for the cytotoxicity of 4HPR that targets on cancer cells with malfunctional UPR. © 2008 Elsevier Inc. All rights reserved.
Persistent Identifierhttp://hdl.handle.net/10722/147574
ISSN
2015 Impact Factor: 3.378
2015 SCImago Journal Rankings: 1.900
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorLai, WLen_US
dc.contributor.authorWong, NSen_US
dc.date.accessioned2012-05-29T06:04:42Z-
dc.date.available2012-05-29T06:04:42Z-
dc.date.issued2008en_US
dc.identifier.citationExperimental Cell Research, 2008, v. 314 n. 8, p. 1667-1682en_US
dc.identifier.issn0014-4827en_US
dc.identifier.urihttp://hdl.handle.net/10722/147574-
dc.description.abstractN-(4-hydroxyphenyl)retinamide (4HPR) is a synthetic retinoid that has been tested in clinical trials as a cancer chemopreventive drug. 4HPR is cytotoxic to cancer cells but the underlying molecular mechanisms are at present only partially understood. Here we demonstrate that in the human cervical cancer cell line HeLa and the human leukemia cell line HL-60, 4HPR caused rapid, Reactive Oxygen Species (ROS)-dependent activation of the Unfolded Protein Response (UPR). In HeLa cells, 4HPR was shown to induce cell death and activation of procaspases. These effects of 4HPR could be abolished by the over-expression of dominant negative mutants of PERK or eIF2α. HeLa cells incubated with 4HPR were found to form autophagosomes that were also mediated by the PERK/eIF2α pathway. While 4HPR-induced cell death could be significantly prevented by the presence of specific caspase inhibitors, 3-methyladenine (3-MA) that inhibits autophagosome formation enhanced 4HPR-induced cell death. Examination of individual 4HPR-treated HeLa cells revealed that those without the development of autophagosomes hence exhibiting an incomplete UPR were caspase-active and were not viable, while those with autophagosomes were caspase-inactive and retained cell viability. Our data suggest that the PERK/eIF2α pathway is essential for the cytotoxicity of 4HPR that targets on cancer cells with malfunctional UPR. © 2008 Elsevier Inc. All rights reserved.en_US
dc.languageengen_US
dc.publisherAcademic Press. The Journal's web site is located at http://www.elsevier.com/locate/yexcren_US
dc.relation.ispartofExperimental Cell Researchen_US
dc.subject.meshActivating Transcription Factor 6 - Metabolismen_US
dc.subject.meshAnticarcinogenic Agents - Antagonists & Inhibitors - Toxicityen_US
dc.subject.meshApoptosisen_US
dc.subject.meshAutophagyen_US
dc.subject.meshCaspase 3 - Metabolismen_US
dc.subject.meshCaspase 9 - Metabolismen_US
dc.subject.meshDna-Binding Proteins - Genetics - Metabolismen_US
dc.subject.meshEndoplasmic Reticulum - Metabolismen_US
dc.subject.meshEnzyme Precursors - Metabolismen_US
dc.subject.meshEukaryotic Initiation Factor-2 - Genetics - Metabolismen_US
dc.subject.meshFenretinide - Antagonists & Inhibitors - Toxicityen_US
dc.subject.meshHl-60 Cellsen_US
dc.subject.meshHela Cellsen_US
dc.subject.meshHumansen_US
dc.subject.meshMolecular Chaperones - Metabolismen_US
dc.subject.meshMutationen_US
dc.subject.meshPhagosomes - Metabolismen_US
dc.subject.meshProtein Foldingen_US
dc.subject.meshRna Splicingen_US
dc.subject.meshSignal Transductionen_US
dc.subject.meshTranscription Factors - Genetics - Metabolismen_US
dc.subject.meshEif-2 Kinase - Genetics - Metabolismen_US
dc.titleThe PERK/eIF2α signaling pathway of Unfolded Protein Response is essential for N-(4-hydroxyphenyl)retinamide (4HPR)-induced cytotoxicity in cancer cellsen_US
dc.typeArticleen_US
dc.identifier.emailWong, NS:nswong@hkucc.hku.hken_US
dc.identifier.authorityWong, NS=rp00340en_US
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.doi10.1016/j.yexcr.2008.02.002en_US
dc.identifier.pmid18342855-
dc.identifier.scopuseid_2-s2.0-42649146188en_US
dc.identifier.hkuros151802-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-42649146188&selection=ref&src=s&origin=recordpageen_US
dc.identifier.volume314en_US
dc.identifier.issue8en_US
dc.identifier.spage1667en_US
dc.identifier.epage1682en_US
dc.identifier.isiWOS:000255624300003-
dc.publisher.placeUnited Statesen_US
dc.identifier.scopusauthoridLai, WL=8563343400en_US
dc.identifier.scopusauthoridWong, NS=7202836641en_US

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