Relationship of growth stimulated by lithium, estradiol, and EGF to phospholipase C activity in MCF-7 human breast cancer cells.
Lithium-stimulated MCF-7 cell proliferation was compared to proliferation stimulated by other mitogens for this cell line-estradiol (E2) and epidermal growth factor (EGF)-and lithium was found to be effective within a narrow concentration range. Mitogenic effects of lithium on proliferation stimulated by E2 and EGF were additive below maximum, but were not synergistic. The phosphoinositide pathway is a cell signaling system involved in cell proliferation, within which phospholipase C (PLC)-mediated hydrolysis of phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P2] leads to the production of the second messengers inositol-1,4,5-trisphosphate [Ins(1,4,5)P3] and diacylglycerol (DAG), as well as to calcium mobilization. At mitogen concentrations which maximally stimulated cell growth, estradiol stimulated both growth and PLC activity, while EGF and lithium stimulated cell growth but had little effect on the activity of the enzyme. Dose-responses with EGF revealed that a low concentration (0.1 ng/ml, 0.017 nM) of EGF appeared to stimulate both PLC activity and cell growth, but that higher concentrations of EGF which stimulated greater proliferation inhibited PLC activity. Steady-state levels of inositol phosphates including inositol trisphosphate were increased by all three mitogens. In growth assays, the phorbol ester phorbol 12-myristate-13-acetate (PMA), which mimics the actions of DAG, stimulated some cell growth, but dioctanoylglycerol, an additional DAG analog, and the calcium ionophore A23187, alone or with the DAG analogs, had no effect. These results suggest that PLC-mediated PtdIns(4,5)P2 hydrolysis is not primarily associated with signaling proliferation by lithium or EGF in MCF-7 breast cancer cells.
Taylor
J A
JA
Department of Veterinary Biomedical Sciences, University of Missouri-Columbia 65211, USA.
Grady
L H
LH
Engler
K S
KS
Welshons
W V
WV
D001943:Breast Neoplasms / Q000201:enzymology* / Q000473:pathology* / Q000503:physiopathology; D002455:Cell Division / Q000187:drug effects; D004075:Diglycerides / Q000096:biosynthesis; D004347:Drug Interactions; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D004958:Estradiol / Q000494:pharmacology*; D006801:Humans; D006868:Hydrolysis; D015544:Inositol 1,4,5-Trisphosphate / Q000096:biosynthesis; D008094:Lithium / Q000494:pharmacology*; D019269:Phosphatidylinositol 4,5-Diphosphate; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013268:Stimulation, Chemical; D014407:Tumor Cells, Cultured / Q000187:drug effects; D010738:Type C Phospholipases / Q000378:metabolism*
D004075:Diglycerides; D019269:Phosphatidylinositol 4,5-Diphosphate; D018129:Phosphatidylinositol Phosphates; D004958:Estradiol; D004815:Epidermal Growth Factor; D015544:Inositol 1,4,5-Trisphosphate; D008094:Lithium; D010738:Type C Phospholipases