p38 MAPK downregulates phosphorylation of Bad in doxorubicin-induced endothelial apoptosis

Simone Grethe, Nadia Coltella, Maria Flavia Di Renzo, M. Isabella Pörn-Ares

Research output: Contribution to journalArticlepeer-review


Doxorubicin is the anthracycline with the widest spectrum of antitumor activity, and it has been shown that the antitumor activity is mediated in vivo by selective triggering of apoptosis in proliferating endothelial cells. We studied cultured human endothelial cells and observed that doxorubicin-induced apoptosis was mediated by p38 mitogen-activated protein kinase (MAPK). Doxorubicin-provoked apoptosis was significantly inhibited by expression of dominant negative p38 MAPK or pharmacological inhibition with SB203580. Furthermore, blocking phosphatidylinositol-3-kinase/Akt signaling significantly increased doxorubicin-induced caspase-3 activity and cell death, indicating that Akt is a survival factor in this system. Notably, we also found that doxorubicin-provoked apoptosis included p38 MAPK-mediated inhibition of Akt and Bad phosphorylation. Furthermore, doxorubicin-stimulated phosphorylation of Bad in cells expressing dominant negative p38 MAPK was impeded by the inhibition of PI3-K. In addition to the impact on Bad phosphorylation, doxorubicin-treatment caused p38 MAPK-dependent downregulation of Bcl-xL protein.

Original languageEnglish
Pages (from-to)781-790
Number of pages10
JournalBiochemical and Biophysical Research Communications
Issue number3
Publication statusPublished - Sep 1 2006


  • Akt
  • Bad
  • Doxorubicin
  • Endothelial cells
  • p38 MAPK

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Molecular Biology


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