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.
Copyright © 2011 UICC.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents, Alkylating / pharmacology*
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Apoptosis
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C-Reactive Protein / genetics
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CCAAT-Enhancer-Binding Protein-alpha / genetics
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CCAAT-Enhancer-Binding Protein-beta / genetics
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Cell Line, Tumor*
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DNA Methylation
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DNA Modification Methylases / deficiency
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DNA Modification Methylases / genetics
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DNA Modification Methylases / metabolism
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DNA Repair
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DNA Repair Enzymes / deficiency
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DNA Repair Enzymes / genetics
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DNA Repair Enzymes / metabolism
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Dacarbazine / analogs & derivatives
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Dacarbazine / pharmacology
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Dioxoles / pharmacology*
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Drug Resistance, Neoplasm
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Fibronectins / genetics
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Humans
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Liposarcoma, Myxoid / drug therapy
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Liposarcoma, Myxoid / genetics*
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Liposarcoma, Myxoid / metabolism*
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Liposarcoma, Myxoid / pathology
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Oncogene Proteins, Fusion / genetics
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Oncogene Proteins, Fusion / metabolism
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Promoter Regions, Genetic
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RNA-Binding Protein FUS / genetics
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RNA-Binding Protein FUS / metabolism
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Serum Amyloid P-Component / genetics
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Signal Transduction
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Temozolomide
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Tetrahydroisoquinolines / pharmacology*
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Trabectedin
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Transcription Factor CHOP / genetics
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Transcription Factor CHOP / metabolism
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Tumor Suppressor Proteins / deficiency
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism
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Ultraviolet Rays
Substances
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Antineoplastic Agents, Alkylating
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CCAAT-Enhancer-Binding Protein-alpha
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CCAAT-Enhancer-Binding Protein-beta
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Dioxoles
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FN1 protein, human
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Fibronectins
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Oncogene Proteins, Fusion
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RNA-Binding Protein FUS
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Serum Amyloid P-Component
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TLS-CHOP fusion protein, human
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Tetrahydroisoquinolines
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Tumor Suppressor Proteins
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Transcription Factor CHOP
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PTX3 protein
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Dacarbazine
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C-Reactive Protein
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DNA Modification Methylases
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MGMT protein, human
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DNA Repair Enzymes
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Trabectedin
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Temozolomide