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 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.

[1]  Weixiong Yang,et al.  Circ_0003489 facilitates multiple myeloma progression by targeting miR-433-3p/PBX3 axis , 2022, Hematology.

[2]  G. Caracciolo,et al.  Impact on NK cell functions of acute versus chronic exposure to extracellular vesicle‐associated MICA: Dual role in cancer immunosurveillance , 2022, Journal of extracellular vesicles.

[3]  T. M. Zanotto,et al.  MicroRNA sequence codes for small extracellular vesicle release and cellular retention , 2021, Nature.

[4]  A. Vacca,et al.  Role of Extracellular Vesicle-Based Cell-to-Cell Communication in Multiple Myeloma Progression , 2021, Cells.

[5]  N. Giannakoulas,et al.  The Role of Marrow Microenvironment in the Growth and Development of Malignant Plasma Cells in Multiple Myeloma , 2021, International journal of molecular sciences.

[6]  S. Stewart,et al.  Unmasking senescence: context-dependent effects of SASP in cancer , 2019, Nature Reviews Cancer.

[7]  K. Crasta,et al.  Exosomes as Emerging Pro-Tumorigenic Mediators of the Senescence-Associated Secretory Phenotype , 2019, International journal of molecular sciences.

[8]  S. Kristensen,et al.  Extracellular vesicle-associated procoagulant phospholipid and tissue factor activity in multiple myeloma , 2019, PloS one.

[9]  Teng Liu,et al.  Tumor-derived extracellular vesicles inhibit osteogenesis and exacerbate myeloma bone disease , 2019, Theranostics.

[10]  N. Suh MicroRNA controls of cellular senescence , 2018, BMB reports.

[11]  A. Santoni,et al.  Drug-Induced Senescent Multiple Myeloma Cells Elicit NK Cell Proliferation by Direct or Exosome-Mediated IL15 Trans-Presentation , 2018, Cancer Immunology Research.

[12]  M. Takasugi Emerging roles of extracellular vesicles in cellular senescence and aging , 2018, Aging cell.

[13]  G. Nelson,et al.  The senescent bystander effect is caused by ROS-activated NF-κB signalling , 2017, Mechanisms of Ageing and Development.

[14]  E. Hara,et al.  Small extracellular vesicles secreted from senescent cells promote cancer cell proliferation through EphA2 , 2017, Nature Communications.

[15]  G. Caracciolo,et al.  Genotoxic stress modulates the release of exosomes from multiple myeloma cells capable of activating NK cell cytokine production: Role of HSP70/TLR2/NF-kB axis , 2017, Oncoimmunology.

[16]  R. Silvestri,et al.  p38 MAPK differentially controls NK activating ligands at transcriptional and post-transcriptional level on multiple myeloma cells , 2017, Oncoimmunology.

[17]  Qiong Wang,et al.  MiR-433-3p suppresses cell growth and enhances chemosensitivity by targeting CREB in human glioma , 2016, Oncotarget.

[18]  G. Bernardini,et al.  Natural killer cell recognition of in vivo drug-induced senescent multiple myeloma cells , 2016, Oncoimmunology.

[19]  R. Westendorp,et al.  Secreted microvesicular miR‐31 inhibits osteogenic differentiation of mesenchymal stem cells , 2016, Aging cell.

[20]  F. Sánchez‐Madrid,et al.  Immunomodulatory role of microRNAs transferred by extracellular vesicles , 2015, Biology of the cell.

[21]  J. O’Sullivan,et al.  Overexpression of the microRNA miR-433 promotes resistance to paclitaxel through the induction of cellular senescence in ovarian cancer cells , 2015, Cancer medicine.

[22]  Tianzhi Yang,et al.  Exosome Delivered Anticancer Drugs Across the Blood-Brain Barrier for Brain Cancer Therapy in Danio Rerio , 2015, Pharmaceutical Research.

[23]  A. Santoni,et al.  Reactive Oxygen Species– and DNA Damage Response–Dependent NK Cell Activating Ligand Upregulation Occurs at Transcriptional Levels and Requires the Transcriptional Factor E2F1 , 2014, The Journal of Immunology.

[24]  F. Sánchez‐Madrid,et al.  Sumoylated hnRNPA2B1 controls the sorting of miRNAs into exosomes through binding to specific motifs , 2013, Nature Communications.

[25]  A. Santoni,et al.  Chemotherapy-elicited upregulation of NKG2D and DNAM-1 ligands as a therapeutic target in multiple myeloma , 2013, Oncoimmunology.

[26]  S. Lowe,et al.  p53-dependent chemokine production by senescent tumor cells supports NKG2D-dependent tumor elimination by natural killer cells , 2013, The Journal of experimental medicine.

[27]  Zhihong Yang,et al.  MicroRNA-433 Inhibits Liver Cancer Cell Migration by Repressing the Protein Expression and Function of cAMP Response Element-binding Protein* , 2013, The Journal of Biological Chemistry.

[28]  F. Wang,et al.  The Tumor Suppressor Roles of miR-433 and miR-127 in Gastric Cancer , 2013, International journal of molecular sciences.

[29]  D. Scadden,et al.  BM mesenchymal stromal cell-derived exosomes facilitate multiple myeloma progression. , 2013, The Journal of clinical investigation.

[30]  H. Tahara,et al.  The role of exosomes and microRNAs in senescence and aging. , 2013, Advanced drug delivery reviews.

[31]  Graça Raposo,et al.  Extracellular vesicles: Exosomes, microvesicles, and friends , 2013, The Journal of cell biology.

[32]  Judith Campisi,et al.  Senescent cells as a source of inflammatory factors for tumor progression , 2010, Cancer and Metastasis Reviews.

[33]  J. Campisi,et al.  The senescence-associated secretory phenotype: the dark side of tumor suppression. , 2010, Annual review of pathology.

[34]  J. Campisi,et al.  Protocols to detect senescence-associated beta-galactosidase (SA-βgal) activity, a biomarker of senescent cells in culture and in vivo , 2009, Nature Protocols.

[35]  R. Foà,et al.  ATM-ATR-dependent up-regulation of DNAM-1 and NKG2D ligands on multiple myeloma cells by therapeutic agents results in enhanced NK-cell susceptibility and is associated with a senescent phenotype. , 2009, Blood.

[36]  Judith Campisi,et al.  Senescence-Associated Secretory Phenotypes Reveal Cell-Nonautonomous Functions of Oncogenic RAS and the p53 Tumor Suppressor , 2008, PLoS biology.

[37]  D. Terrian,et al.  Senescence-associated exosome release from human prostate cancer cells. , 2008, Cancer research.

[38]  S. Lowe,et al.  Senescence of Activated Stellate Cells Limits Liver Fibrosis , 2008, Cell.

[39]  C. Schmitt Senescence, apoptosis and therapy — cutting the lifelines of cancer , 2003, Nature Reviews Cancer.

[40]  A. Palumbo,et al.  Multiple myeloma. , 2011, The New England journal of medicine.