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

doi:10.3390/ijms24076862

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

by

Elisabetta Vulpis

¹,

Lorenzo Cuollo

¹,

Cristiana Borrelli

^1,†,

Fabrizio Antonangeli

²

,

Laura Masuelli

³,

Marco Cippitelli

¹

,

Cinzia Fionda

¹,

Giulio Caracciolo

⁴

,

Maria Teresa Petrucci

⁵

,

Angela Santoni

^1,6,

Alessandra Zingoni

^1,*

and

Alessandra Soriani

^1,*

¹

Department of Molecular Medicine, Sapienza University of Rome, Laboratory Affiliated to Istituto Pasteur Italia—Fondazione Cenci Bolognetti, Viale Regina Elena 291, 00161 Rome, Italy

²

Institute of Molecular Biology and Pathology, National Research Council (CNR), 00161 Rome, Italy

³

Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy

⁴

Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy

⁵

Department of Cellular Biotechnologies and Hematology, Sapienza University of Rome, 00161 Rome, Italy

⁶

IRCCS Neuromed, 86077 Pozzilli, Italy

^*

Authors to whom correspondence should be addressed.

^†

Current address: Swedish Orphan Biovitrum, 20158 Milan, Italy.

Int. J. Mol. Sci. 2023, 24(7), 6862; https://doi.org/10.3390/ijms24076862

Submission received: 28 February 2023 / Revised: 3 April 2023 / Accepted: 5 April 2023 / Published: 6 April 2023

(This article belongs to the Special Issue Cellular Senescence in Physiological and Pathological Processes 2.0)

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Abstract

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.

Keywords: multiple myeloma; senescence; miRNAs; exosomes

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MDPI and ACS Style

Vulpis, E.; Cuollo, L.; Borrelli, C.; Antonangeli, F.; Masuelli, L.; Cippitelli, M.; Fionda, C.; Caracciolo, G.; Petrucci, M.T.; Santoni, A.; et al. Doxorubicin–Mediated miR–433 Expression on Exosomes Promotes Bystander Senescence in Multiple Myeloma Cells in a DDR–Independent Manner. Int. J. Mol. Sci. 2023, 24, 6862. https://doi.org/10.3390/ijms24076862

AMA Style

Vulpis E, Cuollo L, Borrelli C, Antonangeli F, Masuelli L, Cippitelli M, Fionda C, Caracciolo G, Petrucci MT, Santoni A, et al. Doxorubicin–Mediated miR–433 Expression on Exosomes Promotes Bystander Senescence in Multiple Myeloma Cells in a DDR–Independent Manner. International Journal of Molecular Sciences. 2023; 24(7):6862. https://doi.org/10.3390/ijms24076862

Chicago/Turabian Style

Vulpis, Elisabetta, Lorenzo Cuollo, Cristiana Borrelli, Fabrizio Antonangeli, Laura Masuelli, Marco Cippitelli, Cinzia Fionda, Giulio Caracciolo, Maria Teresa Petrucci, Angela Santoni, and et al. 2023. "Doxorubicin–Mediated miR–433 Expression on Exosomes Promotes Bystander Senescence in Multiple Myeloma Cells in a DDR–Independent Manner" International Journal of Molecular Sciences 24, no. 7: 6862. https://doi.org/10.3390/ijms24076862

APA Style

Vulpis, E., Cuollo, L., Borrelli, C., Antonangeli, F., Masuelli, L., Cippitelli, M., Fionda, C., Caracciolo, G., Petrucci, M. T., Santoni, A., Zingoni, A., & Soriani, A. (2023). Doxorubicin–Mediated miR–433 Expression on Exosomes Promotes Bystander Senescence in Multiple Myeloma Cells in a DDR–Independent Manner. International Journal of Molecular Sciences, 24(7), 6862. https://doi.org/10.3390/ijms24076862

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

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