Doxorubicin induces an alarmin-like TLR4-dependent autocrine/paracrine action of Nucleophosmin in human cardiac mesenchymal progenitor cells
Abstract Background Doxorubicin (Dox) is an anti-cancer anthracycline drug that causes double-stranded DNA breaks. It is highly effective against several types of tumours; however, it also has adverse effects on regenerative populations of normal cells, such as human cardiac mesenchymal progenitor c...
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| Format: | Article |
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BMC
2021-06-01
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| Series: | BMC Biology |
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| Online Access: | https://doi.org/10.1186/s12915-021-01058-5 |
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| author | Sara Beji Marco D’Agostino Elisa Gambini Sara Sileno Alessandro Scopece Maria Cristina Vinci Giuseppina Milano Guido Melillo Monica Napolitano Giulio Pompilio Maurizio C. Capogrossi Daniele Avitabile Alessandra Magenta |
| author_facet | Sara Beji Marco D’Agostino Elisa Gambini Sara Sileno Alessandro Scopece Maria Cristina Vinci Giuseppina Milano Guido Melillo Monica Napolitano Giulio Pompilio Maurizio C. Capogrossi Daniele Avitabile Alessandra Magenta |
| author_sort | Sara Beji |
| collection | DOAJ |
| description | Abstract Background Doxorubicin (Dox) is an anti-cancer anthracycline drug that causes double-stranded DNA breaks. It is highly effective against several types of tumours; however, it also has adverse effects on regenerative populations of normal cells, such as human cardiac mesenchymal progenitor cells (hCmPCs), and its clinical use is limited by cardiotoxicity. Another known effect of Dox is nucleolar disruption, which triggers the ubiquitously expressed nucleolar phosphoprotein Nucleophosmin (NPM) to be released from the nucleolus into the cell, where it participates in the orchestration of cellular stress responses. NPM has also been observed in the extracellular space in response to different stress stimuli; however, the mechanism behind this and its functional implications are as yet largely unexplored. The aim of this study was to establish whether Dox could elicit NPM secretion in the extracellular space and to elucidate the mechanism of secretion and the effect of extracellular NPM on hCmPCs. Results We found that following the double-strand break formation in hCmPCs caused by Dox, NPM was rapidly secreted in the extracellular space by an active mechanism, in the absence of either apoptosis or necrosis. Extracellular release of NPM was similarly seen in response to ultraviolet radiation (UV). Furthermore, we observed an increase of NPM levels in the plasma of Dox-treated mice; thus, NPM release also occurred in vivo. The treatment of hCmPCs with extracellular recombinant NPM induced a decrease of cell proliferation and a response mediated through the Toll-like receptor (TLR)4. We demonstrated that NPM binds to TLR4, and via TLR4, and nuclear factor kappa B (NFkB) activation/nuclear translocation, exerts proinflammatory functions by inducing IL-6 and COX-2 gene expression. Finally, we found that in hCmPCs, NPM secretion could be driven by an autophagy-dependent unconventional mechanism that requires TLR4, since TLR4 inhibition dramatically reduced Dox-induced secretion. Conclusions We hypothesise that the extracellular release of NPM could be a general response to DNA damage since it can be elicited by either a chemical agent such as Dox or a physical genotoxic stressor such as UV radiation. Following genotoxic stress, NPM acts similarly to an alarmin in hCmPCs, being rapidly secreted and promoting cell cycle arrest and a TLR4/NFκB-dependent inflammatory response. |
| first_indexed | 2024-12-17T06:48:47Z |
| format | Article |
| id | doaj.art-56f32662462045c09bb2eec58c1f16d5 |
| institution | Directory Open Access Journal |
| issn | 1741-7007 |
| language | English |
| last_indexed | 2024-12-17T06:48:47Z |
| publishDate | 2021-06-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Biology |
| spelling | doaj.art-56f32662462045c09bb2eec58c1f16d52022-12-21T21:59:39ZengBMCBMC Biology1741-70072021-06-0119111610.1186/s12915-021-01058-5Doxorubicin induces an alarmin-like TLR4-dependent autocrine/paracrine action of Nucleophosmin in human cardiac mesenchymal progenitor cellsSara Beji0Marco D’Agostino1Elisa Gambini2Sara Sileno3Alessandro Scopece4Maria Cristina Vinci5Giuseppina Milano6Guido Melillo7Monica Napolitano8Giulio Pompilio9Maurizio C. Capogrossi10Daniele Avitabile11Alessandra Magenta12Experimental Immunology Laboratory, Istituto Dermopatico dell’Immacolata, IDI-IRCCSExperimental Immunology Laboratory, Istituto Dermopatico dell’Immacolata, IDI-IRCCSUnit of Vascular Biology and Regenerative Medicine, Centro Cardiologico Monzino, IRCCSExperimental Immunology Laboratory, Istituto Dermopatico dell’Immacolata, IDI-IRCCSUnit of Vascular Biology and Regenerative Medicine, Centro Cardiologico Monzino, IRCCSUnit of Vascular Biology and Regenerative Medicine, Centro Cardiologico Monzino, IRCCSUnit of Vascular Biology and Regenerative Medicine, Centro Cardiologico Monzino, IRCCSUnit of Cardiology, IDI-IRCCSClinical Epidemiology Unit, IDI-IRCCSUnit of Vascular Biology and Regenerative Medicine, Centro Cardiologico Monzino, IRCCSLaboratory of Cardiovascular Science, National Institute on Aging (NIA), National Institutes of Health (NIH)Idi Farmaceutici S.r.l.National Research Council of Italy (CNR), Institute of Translational Pharmacology IFTAbstract Background Doxorubicin (Dox) is an anti-cancer anthracycline drug that causes double-stranded DNA breaks. It is highly effective against several types of tumours; however, it also has adverse effects on regenerative populations of normal cells, such as human cardiac mesenchymal progenitor cells (hCmPCs), and its clinical use is limited by cardiotoxicity. Another known effect of Dox is nucleolar disruption, which triggers the ubiquitously expressed nucleolar phosphoprotein Nucleophosmin (NPM) to be released from the nucleolus into the cell, where it participates in the orchestration of cellular stress responses. NPM has also been observed in the extracellular space in response to different stress stimuli; however, the mechanism behind this and its functional implications are as yet largely unexplored. The aim of this study was to establish whether Dox could elicit NPM secretion in the extracellular space and to elucidate the mechanism of secretion and the effect of extracellular NPM on hCmPCs. Results We found that following the double-strand break formation in hCmPCs caused by Dox, NPM was rapidly secreted in the extracellular space by an active mechanism, in the absence of either apoptosis or necrosis. Extracellular release of NPM was similarly seen in response to ultraviolet radiation (UV). Furthermore, we observed an increase of NPM levels in the plasma of Dox-treated mice; thus, NPM release also occurred in vivo. The treatment of hCmPCs with extracellular recombinant NPM induced a decrease of cell proliferation and a response mediated through the Toll-like receptor (TLR)4. We demonstrated that NPM binds to TLR4, and via TLR4, and nuclear factor kappa B (NFkB) activation/nuclear translocation, exerts proinflammatory functions by inducing IL-6 and COX-2 gene expression. Finally, we found that in hCmPCs, NPM secretion could be driven by an autophagy-dependent unconventional mechanism that requires TLR4, since TLR4 inhibition dramatically reduced Dox-induced secretion. Conclusions We hypothesise that the extracellular release of NPM could be a general response to DNA damage since it can be elicited by either a chemical agent such as Dox or a physical genotoxic stressor such as UV radiation. Following genotoxic stress, NPM acts similarly to an alarmin in hCmPCs, being rapidly secreted and promoting cell cycle arrest and a TLR4/NFκB-dependent inflammatory response.https://doi.org/10.1186/s12915-021-01058-5DoxorubicinAnthracyclinesUltraviolet radiationAlarminCardiotoxicity |
| spellingShingle | Sara Beji Marco D’Agostino Elisa Gambini Sara Sileno Alessandro Scopece Maria Cristina Vinci Giuseppina Milano Guido Melillo Monica Napolitano Giulio Pompilio Maurizio C. Capogrossi Daniele Avitabile Alessandra Magenta Doxorubicin induces an alarmin-like TLR4-dependent autocrine/paracrine action of Nucleophosmin in human cardiac mesenchymal progenitor cells BMC Biology Doxorubicin Anthracyclines Ultraviolet radiation Alarmin Cardiotoxicity |
| title | Doxorubicin induces an alarmin-like TLR4-dependent autocrine/paracrine action of Nucleophosmin in human cardiac mesenchymal progenitor cells |
| title_full | Doxorubicin induces an alarmin-like TLR4-dependent autocrine/paracrine action of Nucleophosmin in human cardiac mesenchymal progenitor cells |
| title_fullStr | Doxorubicin induces an alarmin-like TLR4-dependent autocrine/paracrine action of Nucleophosmin in human cardiac mesenchymal progenitor cells |
| title_full_unstemmed | Doxorubicin induces an alarmin-like TLR4-dependent autocrine/paracrine action of Nucleophosmin in human cardiac mesenchymal progenitor cells |
| title_short | Doxorubicin induces an alarmin-like TLR4-dependent autocrine/paracrine action of Nucleophosmin in human cardiac mesenchymal progenitor cells |
| title_sort | doxorubicin induces an alarmin like tlr4 dependent autocrine paracrine action of nucleophosmin in human cardiac mesenchymal progenitor cells |
| topic | Doxorubicin Anthracyclines Ultraviolet radiation Alarmin Cardiotoxicity |
| url | https://doi.org/10.1186/s12915-021-01058-5 |
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