Mechanisms of glucocorticoid involvement in mouse lung tumorigenesis.
This report examines a possible mechanism of mouse lung tumor prophylaxis by glucocorticoids (GC). Adrenalectomy (Ax) increased, and corticosterone replacement decreased, lung tumor multiplicity when treatment was begun before administration of the carcinogen, urethan. Ax increased the 3H-thymidine labeling index of alveolar epithelial cells. Tumor multiplicity was also enhanced when urethan was administered during the period of compensatory hyperplasia that occurred in response to lung injury induced by methylcylopentadienyl manganese tricarbonyl. Thus, carcinogen-induced tumor development was amplified by stimulation of division of the target cell population. GC regulation of alveolar epithelial cell proliferation, and hence tumor susceptibility, may be mediated by the Ca++/phospholipid-dependent protein kinase (PKC).The tumor-resistant strain, C57BL/6J, has greater adrenal corticosterone content, higher epithelial cell PKC activity, and lower alveolar epithelial cell proliferation than the tumor-susceptible strain, A/J. In vitro, GC inhibit proliferation of a lung epithelial-derived cell line and increase PKC activity in that cell line. Thus, we hypothesize that GC protect against lung tumor development by increasing PKC content in the epithelial cells from which lung tumors arise; increased intracellular PKC results in decreased epithelial proliferation, and reduces the probability of induction of tumorigenesis by urethan.
Droms
K A
KA
Molecular and Environmental Toxicology Program, School of Pharmacy, University of Colorado, Boulder 80309.
Malkinson
A M
AM
D000311:Adrenal Glands / Q000502:physiology; D000818:Animals; D015153:Blotting, Western; D002455:Cell Division / Q000502:physiology; D002460:Cell Line; D004198:Disease Susceptibility; D004847:Epithelial Cells; D004848:Epithelium / Q000201:enzymology; D005938:Glucocorticoids / Q000502:physiology*; D008175:Lung Neoplasms / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology*; D008345:Manganese; D051379:Mice; D008805:Mice, Inbred A; D008810:Mice, Inbred C57BL; D009942:Organometallic Compounds; D011493:Protein Kinase C / Q000032:analysis; D014520:Urethane
D005938:Glucocorticoids; D009942:Organometallic Compounds; C009907:2-methylcyclopentadienyl manganese tricarbonyl; D014520:Urethane; D008345:Manganese; D011493:Protein Kinase C