The Antiangiogenic Factor 16K PRL Induces Programmed Cell Death in Endothelial Cells by Caspase Activation

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Abstract
We asked whether the antiangiogenic action of 16K human PRL (hPRL), in addition to blocking mitogen- induced vascular endothelial cell proliferation, in- volved activation of programmed cell death. Treat- ment with recombinant 16K hPRL increased DNA fragmentation in cultured bovine brain capillary en- dothelial (BBE) and human umbilical vein endothelial (HUVE) cells in a time- and dose-dependent fashion, independent of the serum concentration. The activa- tion of apoptosis by 16K hPRL was specific for en- dothelial cells, and the activity of the peptide could be inhibited by heat denaturation, trypsin digestion, and immunoneutralization, but not by treatment with the endotoxin blocker, polymyxin-B. 16K hPRL-in- duced apoptosis was correlated with the rapid acti- vation of caspases 1 and 3 and was blocked by phar- macological inhibition of caspase activity. Caspase activation was followed by inactivation of two caspase substrates, poly(ADP-ribose) polymerase (PARP) and the inhibitor of caspase-activated de- oxyribonuclease (DNase) (ICAD). Furthermore, 16K hPRL increased the conversion of Bcl-X to its pro- apoptotic form, suggesting that the Bcl-2 protein family may also be involved in 16K hPRL-induced apoptosis. These findings support the hypothesis that the antiangiogenic action of 16K hPRL includes the activation of programmed cell death of vascular endothelial cells. (Molecular Endocrinology 14: 1536- 1549, 2000)

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