NK cells have an important role in immunosurveillance of multiple myeloma (MM) progression, and their activity is enhanced by combination therapies able to regulate the expression of specific activating ligands. Liver X receptors (LXRs) are nuclear receptors and important regulators of intracellular cholesterol and lipid homeostasis. Moreover, they have regulatory roles in both cancer and immune response. Indeed, they can regulate inflammation and innate and acquired immunity. Furthermore, LXR activation directly acts in cancer cells (e.g., prostate, breast, melanoma, colon cancer, hepatocarcinoma, glioblastoma, and MM) that show an accumulation of cholesterol and alteration of LXR-mediated metabolic pathways. Here, we investigated the role of LXR and cholesterol on the expression of the NK cell-activating ligands major histocompatibility complex class I chain-related molecule A and B (MICA and MICB) in MM cells. The results shown in this work indicate that MM cells are responsive to LXR activation, which induces changes in the intracellular cholesterol content. These changes correlate with an enhanced expression of MICA and MICB in human MM cell lines and in primary malignant plasma cells, 2 ligands of the NK group 2D receptor (NKG2D)/CD314 activating receptor expressed in cytotoxic lymphocytes, rendering MM cells more sensitive to recognition, degranulation, and killing by NK cells. Mechanistically, we observed that LXR activation regulates MICA and MICB expression at different levels: MICA at the transcriptional level, enhancing mica promoter activity, and MICB by inhibiting its degradation in lysosomes. The present study provides evidence that activation of LXR, by enhancing NKG2D ligand expression, can promote NK cell-mediated cytotoxicity and suggests a novel immune-mediated mechanism involving modulation of intracellular cholesterol levels in cancer cells.-Bilotta, M. T., Abruzzese, M. P., Molfetta, R., Scarno, G., Fionda, C., Zingoni, A., Soriani, A., Garofalo, T., Petrucci, M. T., Ricciardi, M. R., Paolini, R., Santoni, A., Cippitelli, M. Activation of liver X receptor up-regulates the expression of the NKG2D ligands MICA and MICB in multiple myeloma through different molecular mechanisms.

Activation of liver X receptor up-regulates the expression of the NKG2D ligands MICA and MICB in multiple myeloma through different molecular mechanisms / Bilotta, Maria Teresa; Abruzzese, Maria Pia; Molfetta, Rosa; Scarno, Gianluca; Fionda, Cinzia; Zingoni, Alessandra; Soriani, Alessandra; Garofalo, Tina; Petrucci, Maria Teresa; Ricciardi, Maria Rosaria; Paolini, Rossella; Santoni, Angela; Cippitelli, Marco. - In: THE FASEB JOURNAL. - ISSN 0892-6638. - 33(2019), pp. 1-6. [10.1096/fj.201900319R]

Activation of liver X receptor up-regulates the expression of the NKG2D ligands MICA and MICB in multiple myeloma through different molecular mechanisms

Bilotta, Maria Teresa;Abruzzese, Maria Pia;Molfetta, Rosa;Scarno, Gianluca;Fionda, Cinzia;Zingoni, Alessandra;Soriani, Alessandra;Garofalo, Tina;Petrucci, Maria Teresa;Ricciardi, Maria Rosaria;Paolini, Rossella;Santoni, Angela
;
Cippitelli, Marco
2019

Abstract

NK cells have an important role in immunosurveillance of multiple myeloma (MM) progression, and their activity is enhanced by combination therapies able to regulate the expression of specific activating ligands. Liver X receptors (LXRs) are nuclear receptors and important regulators of intracellular cholesterol and lipid homeostasis. Moreover, they have regulatory roles in both cancer and immune response. Indeed, they can regulate inflammation and innate and acquired immunity. Furthermore, LXR activation directly acts in cancer cells (e.g., prostate, breast, melanoma, colon cancer, hepatocarcinoma, glioblastoma, and MM) that show an accumulation of cholesterol and alteration of LXR-mediated metabolic pathways. Here, we investigated the role of LXR and cholesterol on the expression of the NK cell-activating ligands major histocompatibility complex class I chain-related molecule A and B (MICA and MICB) in MM cells. The results shown in this work indicate that MM cells are responsive to LXR activation, which induces changes in the intracellular cholesterol content. These changes correlate with an enhanced expression of MICA and MICB in human MM cell lines and in primary malignant plasma cells, 2 ligands of the NK group 2D receptor (NKG2D)/CD314 activating receptor expressed in cytotoxic lymphocytes, rendering MM cells more sensitive to recognition, degranulation, and killing by NK cells. Mechanistically, we observed that LXR activation regulates MICA and MICB expression at different levels: MICA at the transcriptional level, enhancing mica promoter activity, and MICB by inhibiting its degradation in lysosomes. The present study provides evidence that activation of LXR, by enhancing NKG2D ligand expression, can promote NK cell-mediated cytotoxicity and suggests a novel immune-mediated mechanism involving modulation of intracellular cholesterol levels in cancer cells.-Bilotta, M. T., Abruzzese, M. P., Molfetta, R., Scarno, G., Fionda, C., Zingoni, A., Soriani, A., Garofalo, T., Petrucci, M. T., Ricciardi, M. R., Paolini, R., Santoni, A., Cippitelli, M. Activation of liver X receptor up-regulates the expression of the NKG2D ligands MICA and MICB in multiple myeloma through different molecular mechanisms.
2019
LXR; cholesterol; natural killer
01 Pubblicazione su rivista::01a Articolo in rivista
Activation of liver X receptor up-regulates the expression of the NKG2D ligands MICA and MICB in multiple myeloma through different molecular mechanisms / Bilotta, Maria Teresa; Abruzzese, Maria Pia; Molfetta, Rosa; Scarno, Gianluca; Fionda, Cinzia; Zingoni, Alessandra; Soriani, Alessandra; Garofalo, Tina; Petrucci, Maria Teresa; Ricciardi, Maria Rosaria; Paolini, Rossella; Santoni, Angela; Cippitelli, Marco. - In: THE FASEB JOURNAL. - ISSN 0892-6638. - 33(2019), pp. 1-6. [10.1096/fj.201900319R]
File allegati a questo prodotto
File Dimensione Formato  
Bilotta_liver-receptor_2019.pdf

solo gestori archivio

Tipologia: Versione editoriale (versione pubblicata con il layout dell'editore)
Licenza: Tutti i diritti riservati (All rights reserved)
Dimensione 1.95 MB
Formato Adobe PDF
1.95 MB Adobe PDF   Contatta l'autore

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1274659
Citazioni
  • ???jsp.display-item.citation.pmc??? 14
  • Scopus 18
  • ???jsp.display-item.citation.isi??? 17
social impact