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Antimitogenic and Proapoptotic Activities of Methylseleninic Acid in Vascular Endothelial Cells and Associated Effects on PI3K-AKT, ERK, JNK and p38 MAPK Signaling¹

AMC Cancer Research Center, Denver, Colorado 80214 [Z. W., C. J., J. L.], and University of Wisconsin, Madison, Wisconsin 53706 [H. G.]

Inhibiting the mitogenic response of vascular endothelial cells may in part mediate the antiangiogenic and anticancer activity of supranutritional selenium supplements. Our previous work had shown that methylseleninic acid (MSeA), a precursor of the critical anticancer methylselenol metabolite pool, was a potent inhibitor of the growth and survival of human umbilical vein endothelial cells (HUVECs). Here we investigated the effects of MSeA on selected protein kinase signaling transduction pathways to characterize their role in methylselenium induction of HUVEC cell cycle arrest and apoptosis. Exposure of asynchronous HUVECs for 30 h to 3–5 µM MSeA led to a profound G₁ arrest, and exposure to higher levels of MSeA not only led to G₁ arrest but also to DNA fragmentation and caspase-mediated cleavage of poly(ADP-ribose)polymerase, both biochemical hallmarks of apoptosis. Immunoblot analyses indicated that G₁ arrest induced by the sublethal doses of MSeA was associated with dose-dependent reductions of the levels of phospho-protein kinase B (also known as AKT or PKB), phospho-extracellular signal regulated kinase (ERK) 1/2, and phospho-Jun NH₂-terminal kinases 1/2 in the absence of any change in p38 mitogen-activated protein kinase (MAPK) phosphorylation. Apoptosis induced by MSeA was associated with an increased phosphorylation of p38 MAPK in addition to the dephosphorylation of the above kinases. In HUVECs deprived of endothelial cell growth supplement (ECGS) for 48 h, resumption of ECGS stimulation resulted in an 10-fold increase in mitogenic response, as indicated by [³H]thymidine incorporation into DNA. The ECGS-stimulated mitogenic response was inhibited in a dose-dependent manner by MSeA exposure with a IC₅₀ 1 µM and a complete blockage at 3 µM. Wortmannin, an inhibitor of phosphatidylinositol 3-kinase (PI3K) upstream of AKT, potently inhibited the ECGS-stimulated DNA synthesis (IC₅₀, 40 nM). Combining MSeA with Wortmannin showed an additive antimitogenic effect. An inhibitor of MAPK/ERK kinase 1, PD98059, also inhibited ECGS-stimulated DNA synthesis (IC₅₀, 55 µM), but combining PD98059 with MSeA had an effect similar to that when PD98059 was used alone. A time-course experiment indicated that PI3K (AKT and ribosomal protein S6 kinase) activation occurred between 6 and 12 h of ECGS stimulation, and 3 µM MSeA exposure decreased AKT phosphorylation after 12 h of exposure, whereas no inhibitory effect was observed for ERK1/2 phosphorylation throughout the 30-h exposure duration. Additional experiments indicated that MSeA, Wortmannin, or a more specific PI3K inhibitor, LY294002, seemed to target, in the mid- to late-G₁ phase, a common mechanism(s) controlling G₁ progression to S while having no inhibitory effect on DNA synthesis once S-phase had initiated. Taken together, the results support a potent inhibitory activity at achievable serum levels of MSeA on ECGS-stimulated mitogenesis in the mid- to late-G₁ phase, and the target(s) of this inhibitory activity seems to be PI3K or components of this signal pathway. At pharmacological levels of exposure, modulation of ERK1/2 and other protein kinases may be relevant for the proapoptotic action of MSeA.

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