| Autor: |
Soriani A; Department of Molecular Medicine-Istituto Pasteur Italia Fondazione Cenci Bolognetti, Sapienza University of Rome , Rome, Italy., Borrelli C; Department of Molecular Medicine, Center for Life Nano Science@Sapienza, Italian Institute of Technology, Sapienza University of Rome , Rome, Italy., Ricci B; Department of Molecular Medicine-Istituto Pasteur Italia Fondazione Cenci Bolognetti, Sapienza University of Rome, Rome, Italy; Department of Orthopedics, Washington University School of Medicine, St. Louis, MO, USA., Molfetta R; Department of Molecular Medicine-Istituto Pasteur Italia Fondazione Cenci Bolognetti, Sapienza University of Rome , Rome, Italy., Zingoni A; Department of Molecular Medicine-Istituto Pasteur Italia Fondazione Cenci Bolognetti, Sapienza University of Rome , Rome, Italy., Fionda C; Department of Molecular Medicine-Istituto Pasteur Italia Fondazione Cenci Bolognetti, Sapienza University of Rome , Rome, Italy., Carnevale S; Department of Molecular Medicine-Istituto Pasteur Italia Fondazione Cenci Bolognetti, Sapienza University of Rome , Rome, Italy., Abruzzese MP; Department of Molecular Medicine-Istituto Pasteur Italia Fondazione Cenci Bolognetti, Sapienza University of Rome , Rome, Italy., Petrucci MT; Department of Cellular Biotechnologies and Hematology, Sapienza University of Rome , Rome, Italy., Ricciardi MR; Department of Clinical and Molecular Medicine, Sapienza University of Rome , Rome, Italy., La Regina G; Department of Drug Chemistry and Technologies-Isituto Pasteur Italia Fondazione Cenci Bolognetti, Sapienza University of Rome , Rome, Italy., Di Cesare E; Institute of Molecular Biology and Pathology, Sapienza University of Rome, Consiglio Nazionale delle Ricerche (CNR) , Rome, Italy., Lavia P; Institute of Molecular Biology and Pathology, Sapienza University of Rome, Consiglio Nazionale delle Ricerche (CNR) , Rome, Italy., Silvestri R; Department of Drug Chemistry and Technologies-Isituto Pasteur Italia Fondazione Cenci Bolognetti, Sapienza University of Rome , Rome, Italy., Paolini R; Department of Molecular Medicine-Istituto Pasteur Italia Fondazione Cenci Bolognetti, Sapienza University of Rome , Rome, Italy., Cippitelli M; Department of Molecular Medicine-Istituto Pasteur Italia Fondazione Cenci Bolognetti, Sapienza University of Rome , Rome, Italy., Santoni A; Department of Molecular Medicine-Istituto Pasteur Italia Fondazione Cenci Bolognetti, Sapienza University of Rome, Rome, Italy; Neuromed I.R.C.C.S.-Istituto Neurologico Mediterraneo, Pozzilli (IS), Italy. |
| Abstrakt: |
The mechanisms that regulate the expression of the NKG2D and DNAM-1 activating ligands are only partially known, but it is now widely established that their expression is finely regulated at transcriptional, post-transcriptional and post-translational level, and involve numerous stress pathways depending on the type of ligand, stressor, and cell context. We show that treatment of Multiple Myeloma (MM) cells with sub-lethal doses of Vincristine (VCR), an anticancer drug that inhibits the assembly of microtubules, stimulates the expression of NKG2D and DNAM-1 activating ligands, rendering these cells more susceptible to NK cell-mediated killing. Herein, we focused our attention on the identification of the signaling pathways leading to de novo surface expression of ULBP-1, and to MICA and PVR upregulation on VCR-treated MM cells, both at protein and mRNA levels. We found that p38MAPK differentially regulates drug-dependent ligand upregulation at transcriptional and post-transcriptional level. More specifically, we observed that ULBP-1 expression is attributable to both increased transcriptional activity mediated by ATM-dependent p53 activation, and enhanced mRNA stability; while the p38-activated E2F1 transcription factor regulates MICA and PVR mRNA expression. All together, our findings reveal a previously unrecognized activity of VCR as anticancer agent, and indicate that in addition to its established ability to arrest cell growth, VCR can also modulate the expression of NKG2D and DNAM-1 activating ligand on tumor cells and thus promoting NK cell-mediated immunosurveillance. |
