title: Retinoid-mediated stimulation of steroid sulfatase activity in myeloid leukemic cell lines requires RARalpha and RXR and involves the phosphoinositide 3-kinase and ERK-MAP kinase pathways.
abstract: All-trans retinoic acid and 9-cis-retinoic acid stimulate the activity of steroid sulfatase in HL60 acute myeloid leukemia cells in a concentration- and time-dependent manner. Neither of these 'natural retinoids' augmented steroid sulfatase activity in a HL60 sub-line that expresses a dominant-negative retinoic acid receptor alpha (RARalpha). Experiments with synthetic RAR and RXR agonists and antagonists suggest that RARalpha/RXR heterodimers play a role in the retinoid-stimulated increase in steroid sulfatase activity. The retinoid-driven increase in steroid sulfatase activity was attenuated by inhibition of phospholipase D (PLD), but not by inhibitors of phospholipase C. Experiments with inhibitors of protein kinase C (PKC) show that PKCalpha and PKCdelta play an important role in modulating the retinoid-stimulation of steroid sulfatase activity in HL60 cells. Furthermore, we show that pharmacological inhibition of the RAF-1 and ERK MAP kinases blocked the retinoid-stimulated increase in steroid sulfatase activity in HL60 cells and, by contrast, inhibition of the p38-MAP kinase or JNK-MAP kinase had no effect. Pharmacological inhibitors of the phosphatidylinositol 3-kinase, Akt, and PDK-1 also abrogated the retinoid-stimulated increase in steroid sulfatase activity in HL60 cells. These results show that crosstalk between the retinoid-stimulated genomic and non-genomic pathways is necessary to increase steroid sulfatase activity in HL60 cells.
authors.affiliation: Division of Immunity and Infection, The Medical School, University of Birmingham, Edgbaston, Birmingham, B15 2TT, United Kingdom. P.J.Hughes@bham.ac.uk
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Hughes
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhao
authors.forename: Roshantha A
authors.initials: RA
authors.lastname: Chandraratna
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Brown
mesh_terms: D002478:Cells, Cultured; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D018922:HL-60 Cells; D006801:Humans; D007951:Leukemia, Myeloid / Q000201:enzymology*; D020935:MAP Kinase Signaling System; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism* / Q000502:physiology; D010739:Phospholipase D / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000378:metabolism* / Q000502:physiology; D000072482:Retinoic Acid Receptor alpha; D047488:Retinoid X Receptors / Q000378:metabolism; D043266:Steryl-Sulfatase / Q000378:metabolism*; D014162:Transfection; D014212:Tretinoin / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology*
chemical_list: C000607071:RARA protein, human; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D047488:Retinoid X Receptors; D014212:Tretinoin; D011494:Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D010739:Phospholipase D; D043266:Steryl-Sulfatase