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dc.contributor.authorUboldi, S
dc.contributor.authorBernasconi, S
dc.contributor.authorRomano, M
dc.contributor.authorMarchini, S
dc.contributor.authorFuso Nerini, I
dc.contributor.authorDamia, G
dc.contributor.authorGanzinelli, M
dc.contributor.authorMarangon, E
dc.contributor.authorSala, F
dc.contributor.authorClivio, L
dc.contributor.authorChiorino, G
dc.contributor.authorDi Giandomenico, S
dc.contributor.authorRocchi, M
dc.contributor.authorCapozzi, O
dc.contributor.authorMargison, Geoffrey P
dc.contributor.authorWatson, Amanda J
dc.contributor.authorCaccuri, A M
dc.contributor.authorPastore, A
dc.contributor.authorFossati, A
dc.contributor.authorMantovani, R
dc.contributor.authorGrosso, F
dc.contributor.authorTercero, J C
dc.contributor.authorErba, E
dc.contributor.authorD'Incalci, M
dc.date.accessioned2012-11-09T16:54:55Z
dc.date.available2012-11-09T16:54:55Z
dc.date.issued2012-07-01
dc.identifier.citationCharacterization of a new trabectedin-resistant myxoid liposarcoma cell line that shows collateral sensitivity to methylating agents. 2012, 131 (1):59-69 Int J Canceren_GB
dc.identifier.issn1097-0215
dc.identifier.pmid21805478
dc.identifier.doi10.1002/ijc.26340
dc.identifier.urihttp://hdl.handle.net/10541/251615
dc.description.abstractMyxoid Liposarcomas (MLS), characterized by the expression of FUS-CHOP fusion gene are clinically very sensitive to the DNA binding antitumor agent, trabectedin. However, resistance eventually occurs, preventing disease eradication. To investigate the mechanisms of resistance, a trabectedin resistant cell line, 402-91/ET, was developed. The resistance to trabectedin was not related to the expression of MDR related proteins, uptake/efflux of trabectedin or GSH levels that were similar in parental and resistant cells. The 402-91/ET cells were hypersensitive to UV light because of a nucleotide excision repair defect: XPG complementation decreased sensitivity to UV rays, but only partially to trabectedin. 402-91/ET cells showed collateral sensitivity to temozolomide due to the lack of O(6) -methylguanine-DNA-methyltransferase (MGMT) activity, related to the hypermethylation of MGMT promoter. In 402-91 cells chromatin immunoprecipitation (ChIP) assays showed that FUS-CHOP was bound to the PTX3 and FN1 gene promoters, as previously described, and trabectedin caused FUS-CHOP detachment from DNA. Here we report that, in contrast, in 402-91/ET cells, FUS-CHOP was not bound to these promoters. Differences in the modulation of transcription of genes involved in different pathways including signal transduction, apoptosis and stress response between the two cell lines were found. Trabectedin activates the transcription of genes involved in the adipogenic-program such as c/EBPα and β, in 402-91 but not in 402-91/ET cell lines. The collateral sensitivity of 402-91/ET to temozolomide provides the rationale to investigate the potential use of methylating agents in MLS patients resistant to trabectedin.
dc.language.isoenen
dc.rightsArchived with thanks to International journal of cancer. Journal international du canceren_GB
dc.subject.meshAntineoplastic Agents, Alkylating
dc.subject.meshApoptosis
dc.subject.meshC-Reactive Protein
dc.subject.meshCCAAT-Enhancer-Binding Protein-alpha
dc.subject.meshCCAAT-Enhancer-Binding Protein-beta
dc.subject.meshCell Line, Tumor
dc.subject.meshDNA Methylation
dc.subject.meshDNA Modification Methylases
dc.subject.meshDNA Repair
dc.subject.meshDNA Repair Enzymes
dc.subject.meshDacarbazine
dc.subject.meshDioxoles
dc.subject.meshDrug Resistance, Neoplasm
dc.subject.meshFibronectins
dc.subject.meshHumans
dc.subject.meshLiposarcoma, Myxoid
dc.subject.meshOncogene Proteins, Fusion
dc.subject.meshPromoter Regions, Genetic
dc.subject.meshRNA-Binding Protein FUS
dc.subject.meshSerum Amyloid P-Component
dc.subject.meshSignal Transduction
dc.subject.meshTetrahydroisoquinolines
dc.subject.meshTranscription Factor CHOP
dc.subject.meshTumor Suppressor Proteins
dc.subject.meshUltraviolet Rays
dc.titleCharacterization of a new trabectedin-resistant myxoid liposarcoma cell line that shows collateral sensitivity to methylating agents.en
dc.typeArticleen
dc.contributor.departmentDepartment of Oncology, Mario Negri Institute, Via La Masa 19, 20156 Milan, Italy.en_GB
dc.identifier.journalInternational Journal of Canceren_GB
refterms.dateFOA2020-04-20T14:23:15Z
html.description.abstractMyxoid Liposarcomas (MLS), characterized by the expression of FUS-CHOP fusion gene are clinically very sensitive to the DNA binding antitumor agent, trabectedin. However, resistance eventually occurs, preventing disease eradication. To investigate the mechanisms of resistance, a trabectedin resistant cell line, 402-91/ET, was developed. The resistance to trabectedin was not related to the expression of MDR related proteins, uptake/efflux of trabectedin or GSH levels that were similar in parental and resistant cells. The 402-91/ET cells were hypersensitive to UV light because of a nucleotide excision repair defect: XPG complementation decreased sensitivity to UV rays, but only partially to trabectedin. 402-91/ET cells showed collateral sensitivity to temozolomide due to the lack of O(6) -methylguanine-DNA-methyltransferase (MGMT) activity, related to the hypermethylation of MGMT promoter. In 402-91 cells chromatin immunoprecipitation (ChIP) assays showed that FUS-CHOP was bound to the PTX3 and FN1 gene promoters, as previously described, and trabectedin caused FUS-CHOP detachment from DNA. Here we report that, in contrast, in 402-91/ET cells, FUS-CHOP was not bound to these promoters. Differences in the modulation of transcription of genes involved in different pathways including signal transduction, apoptosis and stress response between the two cell lines were found. Trabectedin activates the transcription of genes involved in the adipogenic-program such as c/EBPα and β, in 402-91 but not in 402-91/ET cell lines. The collateral sensitivity of 402-91/ET to temozolomide provides the rationale to investigate the potential use of methylating agents in MLS patients resistant to trabectedin.


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