title: p38 MAPK differentially controls NK activating ligands at transcriptional and post-transcriptional level on multiple myeloma cells.
abstract: 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 tode novosurface 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.
authors.affiliation: Department of Molecular Medicine-Istituto Pasteur Italia Fondazione Cenci Bolognetti, Sapienza University of Rome , Rome, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Soriani
authors.affiliation: Department of Molecular Medicine, Center for Life Nano Science@Sapienza, Italian Institute of Technology, Sapienza University of Rome , Rome, Italy.
authors.forename: Cristiana
authors.initials: C
authors.lastname: Borrelli
authors.affiliation: 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.
authors.forename: Biancamaria
authors.initials: B
authors.lastname: Ricci
authors.affiliation: Department of Molecular Medicine-Istituto Pasteur Italia Fondazione Cenci Bolognetti, Sapienza University of Rome , Rome, Italy.
authors.forename: Rosa
authors.initials: R
authors.lastname: Molfetta
authors.affiliation: Department of Molecular Medicine-Istituto Pasteur Italia Fondazione Cenci Bolognetti, Sapienza University of Rome , Rome, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Zingoni
authors.affiliation: Department of Molecular Medicine-Istituto Pasteur Italia Fondazione Cenci Bolognetti, Sapienza University of Rome , Rome, Italy.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Fionda
authors.affiliation: Department of Molecular Medicine-Istituto Pasteur Italia Fondazione Cenci Bolognetti, Sapienza University of Rome , Rome, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Carnevale
authors.affiliation: Department of Molecular Medicine-Istituto Pasteur Italia Fondazione Cenci Bolognetti, Sapienza University of Rome , Rome, Italy.
authors.forename: Maria Pia
authors.initials: MP
authors.lastname: Abruzzese
authors.affiliation: Department of Cellular Biotechnologies and Hematology, Sapienza University of Rome , Rome, Italy.
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Petrucci
authors.affiliation: Department of Clinical and Molecular Medicine, Sapienza University of Rome , Rome, Italy.
authors.forename: Maria Rosaria
authors.initials: MR
authors.lastname: Ricciardi
authors.affiliation: Department of Drug Chemistry and Technologies-Isituto Pasteur Italia Fondazione Cenci Bolognetti, Sapienza University of Rome , Rome, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: La Regina
authors.affiliation: Institute of Molecular Biology and Pathology, Sapienza University of Rome, Consiglio Nazionale delle Ricerche (CNR) , Rome, Italy.
authors.forename: Erica
authors.initials: E
authors.lastname: Di Cesare
authors.affiliation: Institute of Molecular Biology and Pathology, Sapienza University of Rome, Consiglio Nazionale delle Ricerche (CNR) , Rome, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Lavia
authors.affiliation: Department of Drug Chemistry and Technologies-Isituto Pasteur Italia Fondazione Cenci Bolognetti, Sapienza University of Rome , Rome, Italy.
authors.forename: Romano
authors.initials: R
authors.lastname: Silvestri
authors.affiliation: Department of Molecular Medicine-Istituto Pasteur Italia Fondazione Cenci Bolognetti, Sapienza University of Rome , Rome, Italy.
authors.forename: Rossella
authors.initials: R
authors.lastname: Paolini
authors.affiliation: Department of Molecular Medicine-Istituto Pasteur Italia Fondazione Cenci Bolognetti, Sapienza University of Rome , Rome, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Cippitelli
authors.affiliation: 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.
authors.forename: Angela
authors.initials: A
authors.lastname: Santoni
keywords: Activating ligands; Multiple Myeloma; NK cells; chemo-immunotherapy