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- Publisher Website: 10.1016/j.yexcr.2008.02.002
- Scopus: eid_2-s2.0-42649146188
- PMID: 18342855
- WOS: WOS:000255624300003
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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
Title | The PERK/eIF2α signaling pathway of Unfolded Protein Response is essential for N-(4-hydroxyphenyl)retinamide (4HPR)-induced cytotoxicity in cancer cells |
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Authors | |
Keywords | 4HPR eIF2α PERK Reactive Oxygen Species Unfolded Protein Response |
Issue Date | 2008 |
Publisher | Academic 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? |
Abstract | N-(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 Identifier | http://hdl.handle.net/10722/147574 |
ISSN | 2023 Impact Factor: 3.3 2023 SCImago Journal Rankings: 0.947 |
ISI Accession Number ID | |
References |
DC Field | Value | Language |
---|---|---|
dc.contributor.author | Lai, WL | en_US |
dc.contributor.author | Wong, NS | en_US |
dc.date.accessioned | 2012-05-29T06:04:42Z | - |
dc.date.available | 2012-05-29T06:04:42Z | - |
dc.date.issued | 2008 | en_US |
dc.identifier.citation | Experimental Cell Research, 2008, v. 314 n. 8, p. 1667-1682 | en_US |
dc.identifier.issn | 0014-4827 | en_US |
dc.identifier.uri | http://hdl.handle.net/10722/147574 | - |
dc.description.abstract | N-(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.language | eng | en_US |
dc.publisher | Academic Press. The Journal's web site is located at http://www.elsevier.com/locate/yexcr | en_US |
dc.relation.ispartof | Experimental Cell Research | en_US |
dc.subject | 4HPR | - |
dc.subject | eIF2α | - |
dc.subject | PERK | - |
dc.subject | Reactive Oxygen Species | - |
dc.subject | Unfolded Protein Response | - |
dc.subject.mesh | Activating Transcription Factor 6 - Metabolism | en_US |
dc.subject.mesh | Anticarcinogenic Agents - Antagonists & Inhibitors - Toxicity | en_US |
dc.subject.mesh | Apoptosis | en_US |
dc.subject.mesh | Autophagy | en_US |
dc.subject.mesh | Caspase 3 - Metabolism | en_US |
dc.subject.mesh | Caspase 9 - Metabolism | en_US |
dc.subject.mesh | Dna-Binding Proteins - Genetics - Metabolism | en_US |
dc.subject.mesh | Endoplasmic Reticulum - Metabolism | en_US |
dc.subject.mesh | Enzyme Precursors - Metabolism | en_US |
dc.subject.mesh | Eukaryotic Initiation Factor-2 - Genetics - Metabolism | en_US |
dc.subject.mesh | Fenretinide - Antagonists & Inhibitors - Toxicity | en_US |
dc.subject.mesh | Hl-60 Cells | en_US |
dc.subject.mesh | Hela Cells | en_US |
dc.subject.mesh | Humans | en_US |
dc.subject.mesh | Molecular Chaperones - Metabolism | en_US |
dc.subject.mesh | Mutation | en_US |
dc.subject.mesh | Phagosomes - Metabolism | en_US |
dc.subject.mesh | Protein Folding | en_US |
dc.subject.mesh | Rna Splicing | en_US |
dc.subject.mesh | Signal Transduction | en_US |
dc.subject.mesh | Transcription Factors - Genetics - Metabolism | en_US |
dc.subject.mesh | Eif-2 Kinase - Genetics - Metabolism | en_US |
dc.title | The PERK/eIF2α signaling pathway of Unfolded Protein Response is essential for N-(4-hydroxyphenyl)retinamide (4HPR)-induced cytotoxicity in cancer cells | en_US |
dc.type | Article | en_US |
dc.identifier.email | Wong, NS:nswong@hkucc.hku.hk | en_US |
dc.identifier.authority | Wong, NS=rp00340 | en_US |
dc.description.nature | link_to_subscribed_fulltext | en_US |
dc.identifier.doi | 10.1016/j.yexcr.2008.02.002 | en_US |
dc.identifier.pmid | 18342855 | - |
dc.identifier.scopus | eid_2-s2.0-42649146188 | en_US |
dc.identifier.hkuros | 151802 | - |
dc.relation.references | http://www.scopus.com/mlt/select.url?eid=2-s2.0-42649146188&selection=ref&src=s&origin=recordpage | en_US |
dc.identifier.volume | 314 | en_US |
dc.identifier.issue | 8 | en_US |
dc.identifier.spage | 1667 | en_US |
dc.identifier.epage | 1682 | en_US |
dc.identifier.isi | WOS:000255624300003 | - |
dc.publisher.place | United States | en_US |
dc.identifier.scopusauthorid | Lai, WL=8563343400 | en_US |
dc.identifier.scopusauthorid | Wong, NS=7202836641 | en_US |
dc.identifier.issnl | 0014-4827 | - |