title: Characterization of a new trabectedin-resistant myxoid liposarcoma cell line that shows collateral sensitivity to methylating agents.
abstract: Myxoid 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.
authors.affiliation: Department of Oncology, Mario Negri Institute, Via La Masa 19, 20156 Milan, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Uboldi
authors.forename: S
authors.initials: S
authors.lastname: Bernasconi
authors.forename: M
authors.initials: M
authors.lastname: Romano
authors.forename: S
authors.initials: S
authors.lastname: Marchini
authors.forename: I
authors.initials: I
authors.lastname: Fuso Nerini
authors.forename: G
authors.initials: G
authors.lastname: Damia
authors.forename: M
authors.initials: M
authors.lastname: Ganzinelli
authors.forename: E
authors.initials: E
authors.lastname: Marangon
authors.forename: F
authors.initials: F
authors.lastname: Sala
authors.forename: L
authors.initials: L
authors.lastname: Clivio
authors.forename: G
authors.initials: G
authors.lastname: Chiorino
authors.forename: S
authors.initials: S
authors.lastname: Di Giandomenico
authors.forename: M
authors.initials: M
authors.lastname: Rocchi
authors.forename: O
authors.initials: O
authors.lastname: Capozzi
authors.forename: G P
authors.initials: GP
authors.lastname: Margison
authors.forename: A J
authors.initials: AJ
authors.lastname: Watson
authors.forename: A M
authors.initials: AM
authors.lastname: Caccuri
authors.forename: A
authors.initials: A
authors.lastname: Pastore
authors.forename: A
authors.initials: A
authors.lastname: Fossati
authors.forename: R
authors.initials: R
authors.lastname: Mantovani
authors.forename: F
authors.initials: F
authors.lastname: Grosso
authors.forename: J C
authors.initials: JC
authors.lastname: Tercero
authors.forename: E
authors.initials: E
authors.lastname: Erba
authors.forename: M
authors.initials: M
authors.lastname: D'Incalci
mesh_terms: D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D017209:Apoptosis; D002097:C-Reactive Protein / Q000235:genetics; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000235:genetics; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics; D045744:Cell Line, Tumor; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D004260:DNA Repair; D045643:DNA Repair Enzymes / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000494:pharmacology; D004149:Dioxoles / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D005353:Fibronectins / Q000235:genetics; D006801:Humans; D018208:Liposarcoma, Myxoid / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D034702:RNA-Binding Protein FUS / Q000235:genetics / Q000378:metabolism; D000683:Serum Amyloid P-Component / Q000235:genetics; D015398:Signal Transduction; D000077204:Temozolomide; D044005:Tetrahydroisoquinolines / Q000494:pharmacology*; D000077606:Trabectedin; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D014466:Ultraviolet Rays; D000099153:Pentraxins
chemical_list: D018906:Antineoplastic Agents, Alkylating; D002097:C-Reactive Protein; D022763:CCAAT-Enhancer-Binding Protein-alpha; D022782:CCAAT-Enhancer-Binding Protein-beta; D015254:DNA Modification Methylases; D045643:DNA Repair Enzymes; D003606:Dacarbazine; D004149:Dioxoles; D005353:Fibronectins; D015514:Oncogene Proteins, Fusion; D034702:RNA-Binding Protein FUS; D000683:Serum Amyloid P-Component; D000077204:Temozolomide; D044005:Tetrahydroisoquinolines; D000077606:Trabectedin; D051742:Transcription Factor CHOP; D025521:Tumor Suppressor Proteins; D000099153:Pentraxins; C067625:FN1 protein, human; C106030:TLS-CHOP fusion protein, human; C515491:MGMT protein, human