P38 MAPK and JNK antagonistically control senescence and cytoplasmic p16ink4a expression in doxorubicin-treated endothelial progenitor cells

Paolo Spallarossa, Paola Altieri, Chiara Barisione, Mario Passalacqua, Concetta Aloi, Giuseppina Fugazza, Francesco Frassoni, Marina Podestá, Marco Canepa, Giorgio Ghigliotti, Claudio Brunelli

Research output: Contribution to journalArticle

Abstract

Patients treated with low-dose anthracyclines often show late onset cardiotoxicity. Recent studies suggest that this form of cardiotoxicity is the result of a progenitor cell disease. In this study we demonstrate that Cord Blood Endothelial Progenitor Cells (EPCs) exposed to low, sub-apoptotic doses of doxorubicin show a senescence phenotype characterized by increased SA-b-gal activity, decreased TRF2 and chromosomal abnormalities, enlarged cell shape, and disarrangement of F-actin stress fibers accompanied by impaired migratory ability. P16 INK4A localizes in the cytoplasm of doxorubicin-induced senescent EPCs and not in the nucleus as is the case in EPCs rendered senescent by different stimuli. This localization together with the presence of an arrest in G2, and not at the G1 phase boundary, which is what usually occurs in response to the cell cycle regulatory activity of p16INK4A, suggests that doxorubicin-induced p16 INK4A does not regulate the cell cycle, even though its increase is closely associated with senescence. The effects of doxorubicin are the result of the activation of MAPKs p38 and JNK which act antagonistically. JNK attenuates the senescence, p16 INK4A expression and cytoskeleton remodeling that are induced by activated p38. We also found that conditioned medium from doxorubicin-induced senescent cardiomyocytes does not attract untreated EPCs, unlike conditioned medium from apoptotic cardiomyocytes which has a strong chemoattractant capacity. In conclusion, this study provides a better understanding of the senescence of doxorubicin-treated EPCs, which may be helpful in preventing and treating late onset cardiotoxicity.

Original languageEnglish
Article numbere15583
JournalPLoS One
Volume5
Issue number12
DOIs
Publication statusPublished - 2010

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Fingerprint Dive into the research topics of 'P38 MAPK and JNK antagonistically control senescence and cytoplasmic p16ink4a expression in doxorubicin-treated endothelial progenitor cells'. Together they form a unique fingerprint.

  • Cite this

    Spallarossa, P., Altieri, P., Barisione, C., Passalacqua, M., Aloi, C., Fugazza, G., Frassoni, F., Podestá, M., Canepa, M., Ghigliotti, G., & Brunelli, C. (2010). P38 MAPK and JNK antagonistically control senescence and cytoplasmic p16ink4a expression in doxorubicin-treated endothelial progenitor cells. PLoS One, 5(12), [e15583]. https://doi.org/10.1371/journal.pone.0015583