The antiangiogenic factor 16K human prolactin induces caspase-dependent apoptosis by a mechanism that requires activation of nuclear factor-kappaB.
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-kappaB (NF-kappaB) 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 kappaB-alpha degradation permitting translocation of NF-kappaB to the nucleus and reporter gene activation. Inhibition of NF-kappaB activation by overexpression of a nondegradable inhibitor kappaB-alpha mutant or treatment with NF-kappaB 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-kappaB dependent. These findings support the conclusion that NF-kappaB signaling plays a central role in 16K hPRL-induced apoptosis in vascular endothelial cells.
Tabruyn
Sebastien P
SP
Laboratoire de Biologie Moléculaire et de Génie Génétique, Université de Liège, B-4000 Liège, Belgium.
Sorlet
Catherine M
CM
Rentier-Delrue
Francoise
F
Bours
Vincent
V
Weiner
Richard I
RI
Martial
Joseph A
JA
Struman
Ingrid
I
D017209:Apoptosis / Q000502:physiology*; D020169:Caspases / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism; D006801:Humans; D020672:I-kappa B Proteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010455:Peptides / Q000378:metabolism*; D011388:Prolactin / Q000378:metabolism*
D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D010455:Peptides; D000072000:NF-KappaB Inhibitor alpha; D011388:Prolactin; D020169:Caspases