Trabectedin triggers direct and NK-mediated cytotoxicity in multiple myeloma View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2019-12

AUTHORS

Maria Cucè, Maria Eugenia Gallo Cantafio, Maria Anna Siciliano, Caterina Riillo, Daniele Caracciolo, Francesca Scionti, Nicoletta Staropoli, Valeria Zuccalà, Lorenza Maltese, Anna Di Vito, Katia Grillone, Vito Barbieri, Mariamena Arbitrio, Maria Teresa Di Martino, Marco Rossi, Nicola Amodio, Pierosandro Tagliaferri, Pierfrancesco Tassone, Cirino Botta

ABSTRACT

BACKGROUND: Genomic instability is a feature of multiple myeloma (MM), and impairment in DNA damaging response (DDR) has an established role in disease pathobiology. Indeed, a deregulation of DNA repair pathways may contribute to genomic instability, to the establishment of drug resistance to genotoxic agents, and to the escape from immune surveillance. On these bases, we evaluated the role of different DDR pathways in MM and investigated, for the first time, the direct and immune-mediated anti-MM activity of the nucleotide excision repair (NER)-dependent agent trabectedin. METHODS: Gene-expression profiling (GEP) was carried out with HTA2.0 Affymetrix array. Evaluation of apoptosis, cell cycle, and changes in cytokine production and release have been performed in 2D and 3D Matrigel-spheroid models through flow cytometry on MM cell lines and patients-derived primary MM cells exposed to increasing nanomolar concentrations of trabectedin. DNA-damage response has been evaluated through Western blot, immunofluorescence, and DNA fragmentation assay. Trabectedin-induced activation of NK has been assessed by CD107a degranulation. miRNAs quantification has been done through RT-PCR. RESULTS: By comparing GEP meta-analysis of normal and MM plasma cells (PCs), we observed an enrichment in DNA NER genes in poor prognosis MM. Trabectedin triggered apoptosis in primary MM cells and MM cell lines in both 2D and 3D in vitro assays. Moreover, trabectedin induced DDR activation, cellular stress with ROS production, and cell cycle arrest. Additionally, a significant reduction of MCP1 cytokine and VEGF-A in U266-monocytes co-cultures was observed, confirming the impairment of MM-promoting milieu. Drug-induced cell stress in MM cells led to upregulation of NK activating receptors ligands (i.e., NKG2D), which translated into increased NK activation and degranulation. Mechanistically, this effect was linked to trabectedin-induced inhibition of NKG2D-ligands negative regulators IRF4 and IKZF1, as well as to miR-17 family downregulation in MM cells. CONCLUSIONS: Taken together, our findings indicate a pleiotropic activity of NER-targeting agent trabectedin, which appears a promising candidate for novel anti-MM therapeutic strategies. More... »

PAGES

32

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  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1186/s13045-019-0714-9

    DOI

    http://dx.doi.org/10.1186/s13045-019-0714-9

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1112926644

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/30898137


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