p38 MAPK differentially controls NK activating ligands at transcriptional and post-transcriptional level on multiple myeloma cells

Alessandra Soriani, Cristiana Borrelli, Biancamaria Ricci, Rosa Molfetta, Alessandra Zingoni, Cinzia Fionda, Silvia Carnevale, Maria Pia Abruzzese, Maria Teresa Petrucci, Maria Rosaria Ricciardi, Giuseppe La Regina, Erica Di Cesare, Patrizia Lavia, Romano Silvestri, Rossella Paolini, Marco Cippitelli, Angela Santoni

Research output: Contribution to journalArticle

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 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.

Original languageEnglish
Article numbere1264564
JournalOncoImmunology
Volume6
Issue number1
DOIs
Publication statusPublished - Jan 2 2017

Keywords

  • Activating ligands
  • Chemoimmunotherapy
  • Multiple myeloma
  • NK cells

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Oncology

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    Soriani, A., Borrelli, C., Ricci, B., Molfetta, R., Zingoni, A., Fionda, C., Carnevale, S., Abruzzese, M. P., Petrucci, M. T., Ricciardi, M. R., La Regina, G., Di Cesare, E., Lavia, P., Silvestri, R., Paolini, R., Cippitelli, M., & Santoni, A. (2017). p38 MAPK differentially controls NK activating ligands at transcriptional and post-transcriptional level on multiple myeloma cells. OncoImmunology, 6(1), [e1264564]. https://doi.org/10.1080/2162402X.2016.1264564