FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2553552504> ?p ?o ?g. }

• W2553552504 abstract "Abstract Abstract 3790 Poster Board III-726 TNF-related apoptosis inducing ligand (TRAIL) is a death ligand with selective antitumor activity and minimal cytotoxicity toward non-malignant tissues. TRAIL is under evaluation in several clinical trials in the treatment of diverse cancers, including hematologic malignancies. Molecular mechanisms responsible for acquired TRAIL resistance (e.g. following treatment with TRAIL) are largely unknown. TRAIL-sensitive T-lymphoblastic leukemia cell line Jurkat was cultivated for 8 weeks with TRAIL (1mg/mL). Three TRAIL-resistant Jurkat subclones (TR1-3) were derived and subjected to analysis. Acquired TRAIL-resistance was asociated with decreased sensitivity to several of the tested cytotoxic agents (including TNF-alpha, Fas-ligand, fludarabine and methotrexate), while sensitivity to other agents was unchanged (doxorubicin, cisplatin, etoposid) or even increased (cytarabine). TRAIL-resistant subclones did not show significant differences either in the cell surface expression of death ligand receptors (TRAIL-R1-4, TNF-R, Fas) or in the protein levels of key antiapoptotic regulators (e.g. Bcl2, Mcl1, XIAP, Survivin). Surprisingly, the most prominent finding was significant upregulation of apical proapoptotic caspase 10 (CASP10) in subclone TR1 on mRNA (3-fold increase) as well as on protein level. Moreover, downregulation of CASP8 was detected in subclone TR1 both by western blotting and real-time RT-PCR. siRNA-induced inhibition of protein CASP10 in subclone TR1 was associated with partial restoration of sensitivity to TRAIL-induced apoptosis. No relevant mutations were revealed by sequencing of CASP10 transcript variants A and D of TR1 subclone compared to TRAIL-sensitive Jurkat cells. Immunoprecipitation (IP) analysis of death-inducing signaling complex (DISC) using biotinylated TRAIL suggested impaired DICS formation in subclones TR2 and TR3, but not in TR1. DISC analysis also demonstrated that CASP10 was physically bound in the DISC of TR1 subclone after exposure to TRAIL. Preincubation of the TR subclones with several histone-deacetylase inhibitors (HDACi: vorinostat, sodium valproate or sodium butyrate) for 12 hours almost completely restored sensitivity to TRAIL. Immunoprecipitation analysis of DISC showed treatment with HDACi for 12h resulted in substantially increased binding of precleaved CASP8 (55kD and 43kD) and precleaved CASP10 (53kD) to the DISC. In subclone TR1 pretreatment with HDACi was associated with downregulation of overexpresssed CASP10 mRNA to the levels detected in the original Jurkat cell line. Genome-wide gene-expression profiling using Illumina chips unveiled additional changes in the transcriptome associated with acquired TRAIL resistance. Across all microarrays, the most statistically significant gene expression change was upregulation of Midkine, a heparin-binding growth factor presumably involved in the protection of cancer cells against TRAIL. We showed that acquired TRAIL resistance of Jurkat T-lymphoblastic leukemia cells was associated with complex disruption of both extrinsic and intrinsic apoptotic pathways. While impaired formation of DISC appeared a major molecular mechanism underlying the death-ligand resistance of subclones TR2-3, deregulated expression of apical caspases 8 and 10 substantially contributed to resistance of subclone TR1. RNA interference experiments demonstrated downregulation of otherwise proapoptotic CASP10 functionally impaired extrinsic apoptotic pathway and results in increase apoptotic response to TRAIL. We speculate that displacement of CASP8 by overexpressed CASP10 from DISC might partially block downstream conveying of the proapoptotic signaling from aggregated death receptors. The microarray data implicated that additional molecular deregulations (e.g. overexpression of midkine) associated with acquired TRAIL resistance might contribute to the “multi-drug” resistant phenotype of TRAIL-resistant subclones. The ability of HDACi to restore sensitivity of TRAIL-resistant Jurkat subclones to TRAIL might influence design of novel experimental strategies in the treatment of cancer. Financial Support: LC 06044, MSM 0021620806, MSM 0021620808, GAUK 2009/259153/86309, GAUK 259211/110709 Disclosures: No relevant conflicts of interest to declare." @default.
• W2553552504 created "2016-11-30" @default.
• W2553552504 creator A5001808184 @default.
• W2553552504 creator A5007587640 @default.
• W2553552504 creator A5028671064 @default.
• W2553552504 creator A5030288033 @default.
• W2553552504 creator A5031091474 @default.
• W2553552504 creator A5075324606 @default.
• W2553552504 creator A5082643230 @default.
• W2553552504 creator A5091515333 @default.
• W2553552504 date "2009-11-20" @default.
• W2553552504 modified "2023-10-11" @default.
• W2553552504 title "Upregulation of Caspase 10 Contributes to Acquired Resistance of Acute T-Lymphoblastic Leukemia Cells to Proapoptotic Cytokine TRAIL." @default.
• W2553552504 doi "https://doi.org/10.1182/blood.v114.22.3790.3790" @default.
• W2553552504 hasPublicationYear "2009" @default.
• W2553552504 type Work @default.
• W2553552504 sameAs 2553552504 @default.
• W2553552504 citedByCount "0" @default.
• W2553552504 crossrefType "journal-article" @default.
• W2553552504 hasAuthorship W2553552504A5001808184 @default.
• W2553552504 hasAuthorship W2553552504A5007587640 @default.
• W2553552504 hasAuthorship W2553552504A5028671064 @default.
• W2553552504 hasAuthorship W2553552504A5030288033 @default.
• W2553552504 hasAuthorship W2553552504A5031091474 @default.
• W2553552504 hasAuthorship W2553552504A5075324606 @default.
• W2553552504 hasAuthorship W2553552504A5082643230 @default.
• W2553552504 hasAuthorship W2553552504A5091515333 @default.
• W2553552504 hasConcept C104317684 @default.
• W2553552504 hasConcept C1186008 @default.
• W2553552504 hasConcept C127561419 @default.
• W2553552504 hasConcept C153911025 @default.
• W2553552504 hasConcept C179464577 @default.
• W2553552504 hasConcept C185592680 @default.
• W2553552504 hasConcept C190283241 @default.
• W2553552504 hasConcept C203014093 @default.
• W2553552504 hasConcept C2775975398 @default.
• W2553552504 hasConcept C2776090121 @default.
• W2553552504 hasConcept C31573885 @default.
• W2553552504 hasConcept C33195913 @default.
• W2553552504 hasConcept C48297814 @default.
• W2553552504 hasConcept C502942594 @default.
• W2553552504 hasConcept C55493867 @default.
• W2553552504 hasConcept C66008609 @default.
• W2553552504 hasConcept C86803240 @default.
• W2553552504 hasConcept C8891405 @default.
• W2553552504 hasConcept C98424977 @default.
• W2553552504 hasConceptScore W2553552504C104317684 @default.
• W2553552504 hasConceptScore W2553552504C1186008 @default.
• W2553552504 hasConceptScore W2553552504C127561419 @default.
• W2553552504 hasConceptScore W2553552504C153911025 @default.
• W2553552504 hasConceptScore W2553552504C179464577 @default.
• W2553552504 hasConceptScore W2553552504C185592680 @default.
• W2553552504 hasConceptScore W2553552504C190283241 @default.
• W2553552504 hasConceptScore W2553552504C203014093 @default.
• W2553552504 hasConceptScore W2553552504C2775975398 @default.
• W2553552504 hasConceptScore W2553552504C2776090121 @default.
• W2553552504 hasConceptScore W2553552504C31573885 @default.
• W2553552504 hasConceptScore W2553552504C33195913 @default.
• W2553552504 hasConceptScore W2553552504C48297814 @default.
• W2553552504 hasConceptScore W2553552504C502942594 @default.
• W2553552504 hasConceptScore W2553552504C55493867 @default.
• W2553552504 hasConceptScore W2553552504C66008609 @default.
• W2553552504 hasConceptScore W2553552504C86803240 @default.
• W2553552504 hasConceptScore W2553552504C8891405 @default.
• W2553552504 hasConceptScore W2553552504C98424977 @default.
• W2553552504 hasLocation W25535525041 @default.
• W2553552504 hasOpenAccess W2553552504 @default.
• W2553552504 hasPrimaryLocation W25535525041 @default.
• W2553552504 hasRelatedWork W1451687136 @default.
• W2553552504 hasRelatedWork W1527543121 @default.
• W2553552504 hasRelatedWork W2032605394 @default.
• W2553552504 hasRelatedWork W2038072406 @default.
• W2553552504 hasRelatedWork W2057902579 @default.
• W2553552504 hasRelatedWork W2103234174 @default.
• W2553552504 hasRelatedWork W2137132167 @default.
• W2553552504 hasRelatedWork W2238462180 @default.
• W2553552504 hasRelatedWork W2366982793 @default.
• W2553552504 hasRelatedWork W2521708580 @default.
• W2553552504 hasRelatedWork W2549220183 @default.
• W2553552504 hasRelatedWork W2564325992 @default.
• W2553552504 hasRelatedWork W2566228543 @default.
• W2553552504 hasRelatedWork W2579156720 @default.
• W2553552504 hasRelatedWork W2594935383 @default.
• W2553552504 hasRelatedWork W2747627290 @default.
• W2553552504 hasRelatedWork W2980247094 @default.
• W2553552504 hasRelatedWork W3011315464 @default.
• W2553552504 hasRelatedWork W3183426068 @default.
• W2553552504 hasRelatedWork W1971019939 @default.
• W2553552504 isParatext "false" @default.
• W2553552504 isRetracted "false" @default.
• W2553552504 magId "2553552504" @default.
• W2553552504 workType "article" @default.