Prolactin blocks glucocorticoid induced cell death by inhibiting the disruption of the mitochondrial membrane.
Prolactin (PRL) has been reported to inhibit dexamethasone (Dex) induced cell death. Nevertheless, the mechanism through which PRL exerts its protective effect is still not unravelled. Here, we analyse the effect of PRL at different stages of the glucocorticoid (GC) apoptotic pathway in PRL dependent cells (Nb2 cells). PRL blocks completely the GC induced loss of the mitochondrial transmembrane potential (delta psi(m)) and consequently phosphatidylserine (PS) exposure and loss of DNA content. Although PRL promotes an upregulation of the bcl-2 expression, simultaneous addition of PRL to GC fails to maintain even the normal levels of this anti-apoptotic protein. This finding excludes a critical role for bcl-2 in the PRL protective effect against GC. GC induced delta psi(m) disruption can be inhibited by the ICE-like inhibitor zVAD-fmk but not by ICE inhibitor tetrapeptide acetyl-Tyr-Val-Ala-Asp.chloromethylketone (YVAD-cmk) nor by caspase-3 inhibitor zDEVD. It can be speculated that PRL blocks delta psi(m) disruption by inhibiting an unknown caspase activated by GC.
Weimann
E
E
INSERM Unite 344, Endocrinologie Moleculaire, Paris, France. eweimann@zki.uni-frankfurt.de
Baixeras
E
E
Zamzami
N
N
Kelly
P
P
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D003907:Dexamethasone / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D010450:Endopeptidases / Q000096:biosynthesis / Q000187:drug effects; D004790:Enzyme Induction; D006868:Hydrolysis; D007425:Intracellular Membranes / Q000648:ultrastructure; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000648:ultrastructure*; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000187:drug effects; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011388:Prolactin / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D053148:Caspase 3
D015853:Cysteine Proteinase Inhibitors; D003907:Dexamethasone; D010450:Endopeptidases; D009419:Nerve Tissue Proteins; D011065:Poly(ADP-ribose) Polymerases; D011388:Prolactin; D019253:Proto-Oncogene Proteins c-bcl-2; C505410:Casp3 protein, rat; D053148:Caspase 3