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dc.contributor.authorGupta, S C-
dc.contributor.authorReuter, S-
dc.contributor.authorPhromnoi, K-
dc.contributor.authorPark, B-
dc.contributor.authorHema, P S-
dc.contributor.authorMangalam S Nair-
dc.contributor.authorAggarwal, B B-
dc.date.accessioned2013-11-13T04:14:38Z-
dc.date.available2013-11-13T04:14:38Z-
dc.date.issued2011-
dc.identifier.citationJournal of Biological Chemistry 286(2):1134-1146;14 Jan 2011en_US
dc.identifier.issn0021-9258-
dc.identifier.urihttp://ir.niist.res.in:8080/jspui/handle/123456789/725-
dc.description.abstractTNF-related apoptosis-inducing ligand (TRAIL) shows promise as a cancer treatment, but acquired tumor resistance to TRAIL is a roadblock. Here we investigated whether nimbolide, a limonoid, could sensitize human colon cancer cells to TRAIL. As indicated by assays that measure esterase activity, sub-G(1) fractions, mitochondrial activity, and activation of caspases, nimbolide potentiated the effect of TRAIL. This limonoid also enhanced expression of death receptors (DRs) DR5 and DR4 in cancer cells. Gene silencing of the receptors reduced the effect of limonoid on TRAIL-induced apoptosis. Using pharmacological inhibitors, we found that activation of ERK and p38 MAPK was required for DR up-regulation by nimbolide. Gene silencing of ERK abolished the enhancement of TRAIL-induced apoptosis. Moreover, our studies indicate that the limonoid induced reactive oxygen species production, which was required for ERK activation, up-regulation of DRs, and sensitization to TRAIL; these effects were mimicked by H2O2. In addition, nimbolide down-regulated cell survival proteins, including I-FLICE, cIAP-1, cIAP-2, Bcl-2, Bcl-xL, survivin, and X-linked inhibitor of apoptosis protein, and up-regulated the pro-apoptotic proteins p53 and Bax. Interestingly, p53 and Bax up-regulation by nimbolide was required for sensitization to TRAIL but not for DR up-regulation. Overall, our results indicate that nimbolide can sensitize colon cancer cells to TRAIL-induced apoptosis through three distinct mechanisms: reactive oxygen species- and ERK-mediated up-regulation of DR5 and DR4, downregulation of cell survival proteins, and up-regulation of p53 and Bax.en_US
dc.language.isoenen_US
dc.publisherAmerican Society for Biochemistry and Molecular Biologyen_US
dc.subjectTree Azadirachta-Indicaen_US
dc.subjectInduced apoptosisen_US
dc.subjectHydrogen-peroxideen_US
dc.subjectDown-regulationen_US
dc.subjectMediated apoptosisen_US
dc.subjectAlpha kinaseen_US
dc.subjectTumor-cellsen_US
dc.subjectDNA-damageen_US
dc.subjectResistanceen_US
dc.titleNimbolide sensitizes human colon cancer cells to TRAIL through reactive oxygen species- and ERK-dependent Up-regulation of death receptors, p53, and baxen_US
dc.typeArticleen_US
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