Cargando…

Doxorubicin–Mediated miR–433 Expression on Exosomes Promotes Bystander Senescence in Multiple Myeloma Cells in a DDR–Independent Manner

The success of senescence-based anticancer therapies relies on their anti-proliferative power and on their ability to trigger anti-tumor immune responses. Indeed, genotoxic drug-induced senescence increases the expression of NK cell-activating ligands on multiple myeloma (MM) cells, boosting NK cell...

Descripción completa

Detalles Bibliográficos
Autores principales: Vulpis, Elisabetta, Cuollo, Lorenzo, Borrelli, Cristiana, Antonangeli, Fabrizio, Masuelli, Laura, Cippitelli, Marco, Fionda, Cinzia, Caracciolo, Giulio, Petrucci, Maria Teresa, Santoni, Angela, Zingoni, Alessandra, Soriani, Alessandra
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10095495/
https://www.ncbi.nlm.nih.gov/pubmed/37047835
http://dx.doi.org/10.3390/ijms24076862
_version_ 1785024097261977600
author Vulpis, Elisabetta
Cuollo, Lorenzo
Borrelli, Cristiana
Antonangeli, Fabrizio
Masuelli, Laura
Cippitelli, Marco
Fionda, Cinzia
Caracciolo, Giulio
Petrucci, Maria Teresa
Santoni, Angela
Zingoni, Alessandra
Soriani, Alessandra
author_facet Vulpis, Elisabetta
Cuollo, Lorenzo
Borrelli, Cristiana
Antonangeli, Fabrizio
Masuelli, Laura
Cippitelli, Marco
Fionda, Cinzia
Caracciolo, Giulio
Petrucci, Maria Teresa
Santoni, Angela
Zingoni, Alessandra
Soriani, Alessandra
author_sort Vulpis, Elisabetta
collection PubMed
description The success of senescence-based anticancer therapies relies on their anti-proliferative power and on their ability to trigger anti-tumor immune responses. Indeed, genotoxic drug-induced senescence increases the expression of NK cell-activating ligands on multiple myeloma (MM) cells, boosting NK cell recognition and effector functions. Senescent cells undergo morphological change and context-dependent functional diversification, acquiring the ability to secrete a vast pool of molecules termed the senescence-associated secretory phenotype (SASP), which affects neighboring cells. Recently, exosomes have been recognized as SASP factors, contributing to modulating a variety of cell functions. In particular, evidence suggests a key role for exosomal microRNAs in influencing many hallmarks of cancer. Herein, we demonstrate that doxorubicin treatment of MM cells leads to the enrichment of miR-433 into exosomes, which in turn induces bystander senescence. Our analysis reveals that the establishment of the senescent phenotype on neighboring MM cells is p53- and p21-independent and is related to CDK-6 down-regulation. Notably, miR-433-dependent senescence does not induce the up-regulation of activating ligands on MM cells. Altogether, our findings highlight the possibility of miR-433-enriched exosomes to reinforce doxorubicin-mediated cellular senescence.
format Online
Article
Text
id pubmed-10095495
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-100954952023-04-13 Doxorubicin–Mediated miR–433 Expression on Exosomes Promotes Bystander Senescence in Multiple Myeloma Cells in a DDR–Independent Manner Vulpis, Elisabetta Cuollo, Lorenzo Borrelli, Cristiana Antonangeli, Fabrizio Masuelli, Laura Cippitelli, Marco Fionda, Cinzia Caracciolo, Giulio Petrucci, Maria Teresa Santoni, Angela Zingoni, Alessandra Soriani, Alessandra Int J Mol Sci Brief Report The success of senescence-based anticancer therapies relies on their anti-proliferative power and on their ability to trigger anti-tumor immune responses. Indeed, genotoxic drug-induced senescence increases the expression of NK cell-activating ligands on multiple myeloma (MM) cells, boosting NK cell recognition and effector functions. Senescent cells undergo morphological change and context-dependent functional diversification, acquiring the ability to secrete a vast pool of molecules termed the senescence-associated secretory phenotype (SASP), which affects neighboring cells. Recently, exosomes have been recognized as SASP factors, contributing to modulating a variety of cell functions. In particular, evidence suggests a key role for exosomal microRNAs in influencing many hallmarks of cancer. Herein, we demonstrate that doxorubicin treatment of MM cells leads to the enrichment of miR-433 into exosomes, which in turn induces bystander senescence. Our analysis reveals that the establishment of the senescent phenotype on neighboring MM cells is p53- and p21-independent and is related to CDK-6 down-regulation. Notably, miR-433-dependent senescence does not induce the up-regulation of activating ligands on MM cells. Altogether, our findings highlight the possibility of miR-433-enriched exosomes to reinforce doxorubicin-mediated cellular senescence. MDPI 2023-04-06 /pmc/articles/PMC10095495/ /pubmed/37047835 http://dx.doi.org/10.3390/ijms24076862 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Brief Report
Vulpis, Elisabetta
Cuollo, Lorenzo
Borrelli, Cristiana
Antonangeli, Fabrizio
Masuelli, Laura
Cippitelli, Marco
Fionda, Cinzia
Caracciolo, Giulio
Petrucci, Maria Teresa
Santoni, Angela
Zingoni, Alessandra
Soriani, Alessandra
Doxorubicin–Mediated miR–433 Expression on Exosomes Promotes Bystander Senescence in Multiple Myeloma Cells in a DDR–Independent Manner
title Doxorubicin–Mediated miR–433 Expression on Exosomes Promotes Bystander Senescence in Multiple Myeloma Cells in a DDR–Independent Manner
title_full Doxorubicin–Mediated miR–433 Expression on Exosomes Promotes Bystander Senescence in Multiple Myeloma Cells in a DDR–Independent Manner
title_fullStr Doxorubicin–Mediated miR–433 Expression on Exosomes Promotes Bystander Senescence in Multiple Myeloma Cells in a DDR–Independent Manner
title_full_unstemmed Doxorubicin–Mediated miR–433 Expression on Exosomes Promotes Bystander Senescence in Multiple Myeloma Cells in a DDR–Independent Manner
title_short Doxorubicin–Mediated miR–433 Expression on Exosomes Promotes Bystander Senescence in Multiple Myeloma Cells in a DDR–Independent Manner
title_sort doxorubicin–mediated mir–433 expression on exosomes promotes bystander senescence in multiple myeloma cells in a ddr–independent manner
topic Brief Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10095495/
https://www.ncbi.nlm.nih.gov/pubmed/37047835
http://dx.doi.org/10.3390/ijms24076862
work_keys_str_mv AT vulpiselisabetta doxorubicinmediatedmir433expressiononexosomespromotesbystandersenescenceinmultiplemyelomacellsinaddrindependentmanner
AT cuollolorenzo doxorubicinmediatedmir433expressiononexosomespromotesbystandersenescenceinmultiplemyelomacellsinaddrindependentmanner
AT borrellicristiana doxorubicinmediatedmir433expressiononexosomespromotesbystandersenescenceinmultiplemyelomacellsinaddrindependentmanner
AT antonangelifabrizio doxorubicinmediatedmir433expressiononexosomespromotesbystandersenescenceinmultiplemyelomacellsinaddrindependentmanner
AT masuellilaura doxorubicinmediatedmir433expressiononexosomespromotesbystandersenescenceinmultiplemyelomacellsinaddrindependentmanner
AT cippitellimarco doxorubicinmediatedmir433expressiononexosomespromotesbystandersenescenceinmultiplemyelomacellsinaddrindependentmanner
AT fiondacinzia doxorubicinmediatedmir433expressiononexosomespromotesbystandersenescenceinmultiplemyelomacellsinaddrindependentmanner
AT caracciologiulio doxorubicinmediatedmir433expressiononexosomespromotesbystandersenescenceinmultiplemyelomacellsinaddrindependentmanner
AT petruccimariateresa doxorubicinmediatedmir433expressiononexosomespromotesbystandersenescenceinmultiplemyelomacellsinaddrindependentmanner
AT santoniangela doxorubicinmediatedmir433expressiononexosomespromotesbystandersenescenceinmultiplemyelomacellsinaddrindependentmanner
AT zingonialessandra doxorubicinmediatedmir433expressiononexosomespromotesbystandersenescenceinmultiplemyelomacellsinaddrindependentmanner
AT sorianialessandra doxorubicinmediatedmir433expressiononexosomespromotesbystandersenescenceinmultiplemyelomacellsinaddrindependentmanner