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Trabectedin (ET-743) promotes differentiation in myxoid liposarcoma tumors.

Artikel i vetenskaplig tidskrift
Författare Claudia Forni
Mario Minuzzo
Emanuela Virdis
Elena Tamborini
Matteo Simone
Michele Tavecchio
Eugenio Erba
Federica Grosso
Alessandro Gronchi
Pierre Åman
Paolo Casali
Maurizio D'Incalci
Silvana Pilotti
Roberto Mantovani
Publicerad i Molecular cancer therapeutics
Volym 8
Nummer/häfte 2
Sidor 449-57
ISSN 1535-7163
Publiceringsår 2009
Publicerad vid Institutionen för biomedicin, avdelningen för patologi
Sidor 449-57
Språk en
Länkar dx.doi.org/10.1158/1535-7163.MCT-08...
Ämnesord Adipogenesis, drug effects, genetics, Antineoplastic Agents, pharmacology, Apoptosis, drug effects, CCAAT-Enhancer-Binding Protein-beta, metabolism, Cell Differentiation, drug effects, Cell Line, Tumor, Dioxoles, pharmacology, Drug Screening Assays, Antitumor, Female, Gene Expression Regulation, Neoplastic, drug effects, Humans, Liposarcoma, Myxoid, genetics, pathology, Male, Middle Aged, Oncogene Proteins, Fusion, genetics, Protein Binding, drug effects, RNA-Binding Protein FUS, genetics, Tetrahydroisoquinolines, pharmacology, Transcription Factor CHOP, genetics, Tumor Markers, Biological, metabolism
Ämneskategorier Cancer och onkologi, Kirurgi

Sammanfattning

Differentiation is a complex set of events that can be blocked by rearrangements of regulatory genes producing fusion proteins with altered properties. In the case of myxoid liposarcoma (MLS) tumors, the causative abnormality is a fusion between the CHOP transcription factor and the FUS or EWS genes. CHOP belongs to and is a negative regulator of the large CAAT/enhancer binding protein family whose alpha, beta, and delta members are master genes of adipogenesis. Recent clinical data indicate a peculiar sensitivity of these tumors to the natural marine compound trabectedin. One hypothesis is that the activity of trabectedin is related to the inactivation of the FUS-CHOP oncogene. We find that trabectedin causes detachment of the FUS-CHOP chimera from targeted promoters. Reverse transcription-PCR and chromatin immunoprecipitation analysis in a MLS line and surgical specimens of MLS patients in vivo show activation of the CAAT/enhancer binding protein-mediated transcriptional program that leads to morphologic changes of terminal adipogenesis. The activity is observed in cells with type 1 but not type 8 fusions. Hence, the drug induces maturation of MLS lipoblasts in vivo by targeting the FUS-CHOP-mediated transcriptional block. These data provide a rationale for the specific activity of trabectedin and open the perspective of combinatorial treatments with drugs acting on lipogenic pathways.

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