title: Phosphatidylinositol 3-kinase regulates PMA-induced differentiation and superoxide production in HL-60 cells.
abstract: Treatment of the human promyelocytic leukemia cell line HL-60 with phorbol myristate acetate (PMA) is associated with induction of monocytic or myelocytic differentiation. Since phosphatidylinositol 3-kinase (PI3-kinase) is a critical player in cell proliferation, survival, and differentiation, we studied the role of PI3-kinase during induction of the differentiated monocytic phenotype and superoxide production. In treatment of HL-60 cells with PMA, the PI3-kinase inhibitors LY294002 and wortmannin inhibited cell adhesion and spreading and phagocytic activity. LY294002 and wortmannin also inhibited the proliferation of HL-60 cells. During PMA-induced monocytic differentiation, LY294002 induced apoptosis in a dose dependent manner. The phosphorylation of p85alpha derived from PMA-stimulated HL-60 cells was shown in the time dependent manner. However, p70 S6 kinase inhibitor, rapamycin, did not inhibit PMA-induced monocytic differentiation. During PMA-induced monocytic differentiation, LY294002 inhibited c-jun protein expression and decrease of c-myc protein level. In contrast, LY294002 induced production of superoxide in the HL-60 cells stimulated with forskolin. Moreover, staurosporine and H7, PKC inhibitors, enhanced superoxide production in dibutyryl cAMP-induced HL-60 cells. These results suggest that PI3-kinase may regulate PMA-induced differentiation signal and provide a crucial link between PKC and cAMP in HL-60 cells.
authors.affiliation: Department of Oriental Pharmacy, College of Pharmacy, Center of Oriental Medicinal Science, Iksan, Chonbuk, Republic of Korea.
authors.forename: Sung-Joo
authors.initials: SJ
authors.lastname: Park
authors.forename: Sin-Yol
authors.initials: SY
authors.lastname: Kang
authors.forename: Nam-Song
authors.initials: NS
authors.lastname: Kim
authors.forename: Hyung-Min
authors.initials: HM
authors.lastname: Kim
mesh_terms: D000730:Androstadienes / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D003994:Bucladesine / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002455:Cell Division / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018922:HL-60 Cells; D006801:Humans; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D003994:Bucladesine; D002867:Chromones; D005576:Colforsin; D004791:Enzyme Inhibitors; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011493:Protein Kinase C; D016755:Proto-Oncogene Proteins c-jun; D016271:Proto-Oncogene Proteins c-myc; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D013481:Superoxides; D013755:Tetradecanoylphorbol Acetate; D000077191:Wortmannin; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C448901:ribosomal protein S6 kinase, 70kD, polypeptide 1