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Article: Upregulation of heme oxygenase-1 and p21 confers resistance to apoptosis in human gastric cancer cells

TitleUpregulation of heme oxygenase-1 and p21 confers resistance to apoptosis in human gastric cancer cells
Authors
Issue Date2004
PublisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/onc
Citation
Oncogene, 2004, v. 23 n. 2, p. 503-513 How to Cite?
AbstractBoth heme oxygenase-1 (HO-1) and p21 WAF1/Cip1 (p21) are involved in the pathogenesis of human cancer and their functions are closely associated with apoptosis. However, how these two molecules regulate apoptosis in human gastric cancer is unknown. In this study, we studied how HO-1 and p21 were regulated in two gastric cancer cell lines, MKN-45 with wild p53 and MKN-28 with mutant p53. The cells were treated with hemin and cadmium to induce HO-1. The result showed that HO-1 protein was significantly induced by hemin and cadmium in both cells tested. Following the HO-1 expression, p21 level was also markedly induced. The cells with increased HO-1 and p21 showed obviously resistantance to apoptotic stimuli. The levels of HO-1 and p21 induced were significantly inhibited by p38 mitogen-activated protein kinase (p38 MAPK) inhibitor (SB203580) and extracellular-regulated kinase (ERK) inhibitor (PD098059). Parallel to decreased HO-1 and p21 expression, the kinase inhibitors also significantly attenuated the resistance of the cells to apoptosis. The elevated HO-1 and p21 was further found to be associated with increase activity of the nuclear NF-κB and the inhibition of NF-κB led to the block of their induction. The elevated HO-1 and p21 were also demonstrated to be related to increased cellular inhibitor of caspase inbitory protein-2 (c-IAP2) and decreased caspapse-3 activity. It was noted that the above changes observed were not different between MKN-45 and MKN-28 cells, suggesting the functions of HO-1 and p21 were irrespective of the status of p53. In conclusion, we demonstrate that the resistance to apoptosis in gastric cancer cells with elevated HO-1 and p21 is independent of p53 status in a p38 MAPK- and ERK-mediated pathway with elevated C-IAP2 and decreased caspase-3 activity and that this pathway is sensitive to the inhibition of NF-κB.
Persistent Identifierhttp://hdl.handle.net/10722/162756
ISSN
2015 Impact Factor: 7.932
2015 SCImago Journal Rankings: 4.047
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorLiu, ZMen_US
dc.contributor.authorChen, GGen_US
dc.contributor.authorNg, EKWen_US
dc.contributor.authorLeung, WKen_US
dc.contributor.authorSung, JJYen_US
dc.contributor.authorChung, SCSen_US
dc.date.accessioned2012-09-05T05:23:07Z-
dc.date.available2012-09-05T05:23:07Z-
dc.date.issued2004en_US
dc.identifier.citationOncogene, 2004, v. 23 n. 2, p. 503-513en_US
dc.identifier.issn0950-9232en_US
dc.identifier.urihttp://hdl.handle.net/10722/162756-
dc.description.abstractBoth heme oxygenase-1 (HO-1) and p21 WAF1/Cip1 (p21) are involved in the pathogenesis of human cancer and their functions are closely associated with apoptosis. However, how these two molecules regulate apoptosis in human gastric cancer is unknown. In this study, we studied how HO-1 and p21 were regulated in two gastric cancer cell lines, MKN-45 with wild p53 and MKN-28 with mutant p53. The cells were treated with hemin and cadmium to induce HO-1. The result showed that HO-1 protein was significantly induced by hemin and cadmium in both cells tested. Following the HO-1 expression, p21 level was also markedly induced. The cells with increased HO-1 and p21 showed obviously resistantance to apoptotic stimuli. The levels of HO-1 and p21 induced were significantly inhibited by p38 mitogen-activated protein kinase (p38 MAPK) inhibitor (SB203580) and extracellular-regulated kinase (ERK) inhibitor (PD098059). Parallel to decreased HO-1 and p21 expression, the kinase inhibitors also significantly attenuated the resistance of the cells to apoptosis. The elevated HO-1 and p21 was further found to be associated with increase activity of the nuclear NF-κB and the inhibition of NF-κB led to the block of their induction. The elevated HO-1 and p21 were also demonstrated to be related to increased cellular inhibitor of caspase inbitory protein-2 (c-IAP2) and decreased caspapse-3 activity. It was noted that the above changes observed were not different between MKN-45 and MKN-28 cells, suggesting the functions of HO-1 and p21 were irrespective of the status of p53. In conclusion, we demonstrate that the resistance to apoptosis in gastric cancer cells with elevated HO-1 and p21 is independent of p53 status in a p38 MAPK- and ERK-mediated pathway with elevated C-IAP2 and decreased caspase-3 activity and that this pathway is sensitive to the inhibition of NF-κB.en_US
dc.languageengen_US
dc.publisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/oncen_US
dc.relation.ispartofOncogeneen_US
dc.subject.meshApoptosis - Drug Effectsen_US
dc.subject.meshCadmium - Pharmacologyen_US
dc.subject.meshCaspase 3en_US
dc.subject.meshCaspases - Metabolismen_US
dc.subject.meshCell Division - Drug Effectsen_US
dc.subject.meshCell Line, Tumoren_US
dc.subject.meshCyclin-Dependent Kinase Inhibitor P21en_US
dc.subject.meshCyclins - Metabolismen_US
dc.subject.meshFlavonoids - Pharmacologyen_US
dc.subject.meshG0 Phase - Drug Effectsen_US
dc.subject.meshG1 Phase - Drug Effectsen_US
dc.subject.meshGene Expression Regulation, Neoplastic - Drug Effectsen_US
dc.subject.meshHeme Oxygenase (Decyclizing) - Metabolismen_US
dc.subject.meshHeme Oxygenase-1en_US
dc.subject.meshHemin - Pharmacologyen_US
dc.subject.meshHumansen_US
dc.subject.meshImidazoles - Pharmacologyen_US
dc.subject.meshMembrane Proteinsen_US
dc.subject.meshMitogen-Activated Protein Kinases - Antagonists & Inhibitors - Metabolismen_US
dc.subject.meshNf-Kappa B - Metabolismen_US
dc.subject.meshProteins - Metabolismen_US
dc.subject.meshPyridines - Pharmacologyen_US
dc.subject.meshStomach Neoplasms - Enzymology - Genetics - Metabolism - Pathologyen_US
dc.subject.meshUp-Regulation - Drug Effectsen_US
dc.titleUpregulation of heme oxygenase-1 and p21 confers resistance to apoptosis in human gastric cancer cellsen_US
dc.typeArticleen_US
dc.identifier.emailLeung, WK:waikleung@hku.hken_US
dc.identifier.authorityLeung, WK=rp01479en_US
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.doi10.1038/sj.onc.1207173en_US
dc.identifier.pmid14647439-
dc.identifier.scopuseid_2-s2.0-0842308302en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-0842308302&selection=ref&src=s&origin=recordpageen_US
dc.identifier.volume23en_US
dc.identifier.issue2en_US
dc.identifier.spage503en_US
dc.identifier.epage513en_US
dc.identifier.isiWOS:000188098300021-
dc.publisher.placeUnited Kingdomen_US
dc.identifier.scopusauthoridLiu, ZM=7406671362en_US
dc.identifier.scopusauthoridChen, GG=35291566400en_US
dc.identifier.scopusauthoridNg, EKW=7201647539en_US
dc.identifier.scopusauthoridLeung, WK=7201504523en_US
dc.identifier.scopusauthoridSung, JJY=24473715000en_US
dc.identifier.scopusauthoridChung, SCS=19642462800en_US

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