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The Antiangiogenic Factor 16K Human Prolactin Induces Caspase-Dependent Apoptosis by a Mechanism that Requires Activation of Nuclear Factor-B

Laboratoire de Biologie Moléculaire et de Génie Génétique (S.P.T., C.M.S., F.R.-D., J.A.M., I.S.) and Génétique Humaine (V.B.), Université de Liège, B-4000 Liège, Belgium; and Center for Reproductive Sciences (R.I.W.), Department of Obstetrics, Gynecology and Reproductive Sciences, University of California School of Medicine, San Francisco, California 94143

Address all correspondence and requests for reprints to: Joseph Martial, Laboratoire de Biologie Moléculaire et de Génie Génétique, Université de Liège, Allée du 6 Aout B6A, B-4000 Liège, Belgium. E-mail: jmartial{at}ulg.ac.be.

We have previously shown that the 16-kDa N-terminal fragment of human prolactin (16K hPRL) has antiangiogenic properties, including the ability to induce apoptosis in vascular endothelial cells. Here, we examined whether the nuclear factor-B (NF-B) signaling pathway was involved in mediating the apoptotic action of 16K hPRL in bovine adrenal cortex capillary endothelial cells. In a dose-dependent manner, treatment with 16K hPRL induced inhibitor B- degradation permitting translocation of NF-B to the nucleus and reporter gene activation. Inhibition of NF-B activation by overexpression of a nondegradable inhibitor B- mutant or treatment with NF-B inhibitors blocked 16K hPRL-induced apoptosis. Treatment with 16K hPRL activated the initiator caspases-8 and -9 and the effector caspase-3, all of which were essential for stimulation of DNA fragmentation. This activation of the caspase cascade by 16K hPRL was also NF-B dependent. These findings support the conclusion that NF-B signaling plays a central role in 16K hPRL-induced apoptosis in vascular endothelial cells.

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