Premium
IAP antagonization promotes inflammatory destruction of vascular endothelium
Author(s) -
Witt Axel,
Seeger Jens M,
Coutelle Oliver,
Zigrino Paola,
Broxtermann Pia,
Andree Maria,
Brinkmann Kerstin,
Jüngst Christian,
Schauss Astrid C,
Schüll Stephan,
Wohlleber Dirk,
Knolle Percy A,
Krönke Martin,
Mauch Cornelia,
Kashkar Hamid
Publication year - 2015
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.201439616
Subject(s) - endothelium , microbiology and biotechnology , biology , genetics
In this study, we show for the first time that the therapeutic antagonization of inhibitor of apoptosis proteins ( IAP s) inhibits B16 melanoma growth by disrupting tumor vasculature. Specifically, the treatment of mice bearing B16 melanoma with an IAP antagonist compound A (Comp A) inhibits tumor growth not by inducing direct cytotoxicity against B16 cells but rather by a hitherto unrecognized antiangiogenic activity against tumor vessels. Our detailed analysis showed that Comp A treatment induces NF ‐κB activity in B16 tumor cells and facilitates the production of TNF . In the presence of Comp A, endothelial cells ( EC s) become highly susceptible to TNF and undergo apoptotic cell death. Accordingly, the antiangiogenic and growth‐attenuating effects of Comp A treatment were completely abolished in TNF ‐R knockout mice. This novel targeting approach could be of clinical value in controlling pathological neoangiogenesis under inflammatory condition while sparing blood vessels under normal condition.