Lipocortin 1 mediates dexamethasone-induced growth arrest of the A549 lung adenocarcinoma cell line.
The synthetic glucocorticoid dexamethasone (1 microM to 1 pM) strongly (maximum greater than 80%) inhibits proliferation of the A549 human lung adenocarcinoma line (EC50 greater than 1 nM) and leads to the appearance, or a further increase (approximately 3-fold) in the expression on the cell surface, of the calcium and phospholipid binding protein lipocortin (annexin) 1. Both these effects, which are shared by hydrocortisone (1 microM) but not by progesterone or aldosterone (1 microM), are inhibited by the antiglucocorticoids RU38486 and RU43044 (1 microM). The nonsteroidal antiinflammatory drugs indomethacin (1 microM) and naproxen (10 microM) and human recombinant lipocortin 1 (0.05-5.0 micrograms/ml) also produce growth arrest in this cell line. During proliferation A549 cells spontaneously release prostaglandin E2 [10-20 ng (28-57 pmol) per ml per 5-day period] into the growth medium. In concentrations that cause growth-arrest, dexamethasone, indomethacin, and lipocortin 1 abolish the generation of this eicosanoid by A549 cells. Prostaglandin E2 itself (0.01-1 pM) stimulates cell growth and partially reverses (approximately 50%) the inhibition of growth caused by dexamethasone and indomethacin. Addition of the neutralizing anti-lipocortin 1 monoclonal antibody 1A (5 micrograms/ml), but not the nonneutralizing anti-lipocortin monoclonal antibody 1B, substantially reversed (greater than 80%) the inhibitory activity of dexamethasone on both growth and prostaglandin E2 synthesis. The generation of prostaglandin E2 by A549 cells seems to be an important regulator of cell proliferation in vitro and the dexamethasone-induced suppression of proliferation in this model is attributable to eicosanoid inhibition caused by lipocortin 1.
Croxtall
J D
JD
Department of Biochemical Pharmacology, William Harvey Research Institute, Medical College, St. Bartholomew's Hospital, London, United Kingdom.
Flower
R J
RJ
D000230:Adenocarcinoma; D000450:Aldosterone / Q000494:pharmacology; D017302:Annexins; D000911:Antibodies, Monoclonal; D002135:Calcium-Binding Proteins / Q000096:biosynthesis / Q000494:pharmacology / Q000502:physiology*; D002455:Cell Division / Q000187:drug effects / Q000502:physiology*; D002462:Cell Membrane / Q000187:drug effects / Q000502:physiology; D003907:Dexamethasone / Q000494:pharmacology*; D015232:Dinoprostone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D006854:Hydrocortisone / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D007700:Kinetics; D008175:Lung Neoplasms; D015735:Mifepristone / Q000494:pharmacology; D009288:Naproxen / Q000494:pharmacology; D010740:Phospholipases / Q000037:antagonists & inhibitors; D011374:Progesterone / Q000494:pharmacology; D011994:Recombinant Proteins / Q000494:pharmacology
D017302:Annexins; D000911:Antibodies, Monoclonal; D002135:Calcium-Binding Proteins; D011994:Recombinant Proteins; D015735:Mifepristone; D000450:Aldosterone; D011374:Progesterone; D009288:Naproxen; D003907:Dexamethasone; D010740:Phospholipases; D015232:Dinoprostone; D006854:Hydrocortisone; D007213:Indomethacin