Methyl selenium-induced vascular endothelial apoptosis is executed by caspases and principally mediated by p38 MAPK pathway.
The induction of vascular endothelial cell apoptosis and inhibition of tumor-associated angiogenesis by selenium may contribute to its cancer chemopreventive effects. Here we examined the stress-activated/mitogen-activated protein kinases (p38 MAPK, ERK1/2) and protein kinase B/AKT as potential signaling mediators for apoptosis induction by a methylselenol precursor methylseleninic acid (MSeA) in human umbilical vein endothelial cells (HUVEC). Time course experiments showed that p38 MAPK hyperphosphorylation and ERK1/2 dephosphorylation occurred before the cleavage of procaspase-3 and poly(ADP-ribose) polymerase (PARP), whereas AKT dephosphorylation occurred after caspase activation. The p38 MAPK inhibitor SB202190 attenuated the MSeA-induced morphological changes and decreased DNA fragmentation and the cleavage of procaspase-3 and PARP in concordant proportions. The general caspase inhibitor zVADfmk completely blocked the MSeA-induced PARP cleavage and DNA fragmentation, whereas zDEVDfmk, an inhibitor for caspase-3-like activities, was nearly as effective for inhibiting apoptosis. In comparison, apoptosis induced by selenite in HUVECs was observed in the complete absence of an activation of the major caspases. Taken together, the data support p38 MAPK as a key upstream mediator for the methylselenol-specific induction of vascular endothelial caspase-dependent apoptosis, which is principally executed by caspase-3-like activities.
The Hormel Institute, University of Minnesota, Austin, MN 55912, USA.
Cheng
C
Jiang
Ki-Hwan
KH
Kim
Zaisen
Z
Wang
Junxuan
J
Lü
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3; D020169:Caspases / Q000187:drug effects / Q000378:metabolism*; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology*; D006801:Humans; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D012643:Selenium / Q000494:pharmacology*; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism*
D011518:Proto-Oncogene Proteins; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D048051:p38 Mitogen-Activated Protein Kinases; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D012643:Selenium