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

• 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.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Kirurgi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Surgery (hsv//eng)

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Cancer och onkologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Cancer and Oncology (hsv//eng)

Nyckelord

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

Publikations- och innehållstyp

ref (ämneskategori)

art (ämneskategori)