Dehydroepiandrosterone inhibits the proliferation of human umbilical vein endothelial cells by enhancing the expression of p53 and p21, restricting the phosphorylation of retinoblastoma protein, and is androgen- and estrogen-receptor independent.
Dehydroepiandrosterone (DHEA), a steroid hormone, modified the proliferation of human umbilical vein endothelial cells in a dose-dependent manner. Its inactive sulfate ester (DHEA-S) and two of its metabolites -- estradiol and testosterone -- had no inhibitory effect at physiological concentrations. Antiproliferation was associated with arrest in the G1 phase of the cell cycle, but not with cell death, as evaluated by cleavage of poly(ADP-ribose) polymerase and exposure of phosphatidylserine. The effect was not blocked by inhibitors of androgen or estrogen receptors. DHEA diminished the levels of phosphorylated retinoblastoma protein and increased the expression of p53 and p21 mRNAs. These results show that DHEA inhibits endothelial cell proliferation by regulating cell cycle relevant proteins through a cytoplasmic steroid hormone-independent pathway.
Zapata
Estrella
E
Departamento de Biología Celular, Instituto Nacional de Cardiología Ignacio Chávez, Mexico DF, Mexico.
Ventura
José L
JL
De la Cruz
Karina
K
Rodriguez
Emma
E
Damián
Pablo
P
Massó
Felipe
F
Montaño
Luis F
LF
López-Marure
Rebeca
R
D018797:Cell Cycle Proteins / Q000187:drug effects / Q000235:genetics*; D002455:Cell Division / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004247:DNA / Q000096:biosynthesis; D003687:Dehydroepiandrosterone / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D004791:Enzyme Inhibitors; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D010766:Phosphorylation; D012333:RNA, Messenger / Q000235:genetics; D011944:Receptors, Androgen / Q000502:physiology; D011960:Receptors, Estrogen / Q000502:physiology*; D016160:Retinoblastoma Protein / Q000187:drug effects / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013936:Thymidine / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000187:drug effects / Q000235:genetics*; D014471:Umbilical Veins
C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D011944:Receptors, Androgen; D011960:Receptors, Estrogen; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53; D003687:Dehydroepiandrosterone; D004247:DNA; D013936:Thymidine