Wortmannin inhibits serum-induced activation of phosphoinositide 3-kinase and proliferation of CHRF-288 cells.
Activated phosphoinositide 3-kinase has been suggested to be involved in cytoskeletal reorganization and mitogenesis. Lysophosphatidic acid has been found to trigger several "classic" signal transduction pathways and also accounts for the ability of serum to stimulate focal adhesion and stress fiber formation in fibroblasts. We present evidence that serum or lysophosphatidic acid activates phosphoinositide 3-kinase in CHRF-288 cells (a leukemic cell line derived from megakaryoblasts), leading to transient accumulation of phosphatidylinositol(3,4,5)P3 and increased phosphatidylinositol(3,4)P2, and stimulates phospholipase C. Exposure of CHRF cells to serum promotes cell proliferation, whereas exposure to lysophosphatidic acid does not. Wortmannin, a potent inhibitor of phosphoinositide 3-kinase, inhibits 3-phosphorylated phosphoinositide accumulation and cell proliferation without inhibiting phospholipase C. We propose that activation of phosphoinositide 3-kinase is required for the full proliferative response of CHRF cells exposed to serum but, as gauged by our findings for lysophosphatidic acid, not sufficient to induce proliferation.
Vemuri
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Department of Pharmacology, Jefferson Cancer Institute/Cardeza Foundation for Hematologic Research, Philadelphia, PA 19107.
Rittenhouse
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SE
D000730:Androstadienes / Q000494:pharmacology*; D001769:Blood; D002455:Cell Division / Q000187:drug effects*; D004789:Enzyme Activation; D006801:Humans; D008246:Lysophospholipids / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D000077191:Wortmannin
D000730:Androstadienes; D008246:Lysophospholipids; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); D000077191:Wortmannin