Although the goals of our project, namely, the elucidation of the mechanism of extragenomic effects of glucocorticoids on lipid biosynthesis, have remained unchanged, our work has recently acquired a new dimension. We have obtained two clonal lines of human acute leukemia cells, one dexamethasone-sensitive and one dexamethasone-resistant, but both containing a functional glucocorticoid receptor system. This presents an opportunity to directly check the relevance of our data to the mechanism of the lymphocytolytic effects of glycocorticoids without the encumberance of alterations due to receptor behavior. Preliminary study of the two above mentioned acute lymphocytic leukemia lines has revealed a striking difference in their capacity to synthesize cholesterol, the resistant line being much more active than the sensitive. Also, the inhibitory effect of dexamethasone on cholesterol synthesis from acetate was much more pronounced in the sensitive than in the resistant line. On a time basis, the effect occurred together with the observed cell shrinkage but preceded the effect on protein synthesis and cell division. Some similarity between the effects of compactin, a competitive inhibitor of HMG-CoA reductase, and dexamethasone was revealed in a dex-sensitive line of chronic lymphocytic leukemia. Both compounds caused decreased formation of cholesterol/filipin complexes in the membranes with inhibition partly reversible by mevalonate. It is noteworthy that the effects were evident in both delipidized and non-delipidized serum-supplemented medium pointing to the possibility that in these cells plasma membrane cholesterol is derived predominantly from de novo synthesis rather than from serum lipoproteins. The temporal changes following addition of dexamethasone to both resistant and sensitive cells are now being studied. The prameters measured include DNA, protein and cholesterol synthesis as well as the formation of autocrine growth factor(s) resembling interleukin-2. (D)

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA008315-23
Application #
3163300
Study Section
Pathology B Study Section (PTHB)
Project Start
1985-05-01
Project End
1989-04-30
Budget Start
1987-05-01
Budget End
1988-04-30
Support Year
23
Fiscal Year
1987
Total Cost
Indirect Cost
Name
University of Kansas
Department
Type
Schools of Medicine
DUNS #
016060860
City
Kansas City
State
KS
Country
United States
Zip Code
66160
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