The objective of this research project is to establish temporal and causal relationship between glucocorticoid-induced programmed cell death (apoptosis) and the effect of this group of steroids of cholesterol and dolichol synthesis. Two cell lines derived from human acute T-cell leukemia will be used. Although one line (CEM- C7) is glucocorticoid-sensitive and the other line (CEM-Cl) is glucocorticoid-resistant, both lines have specific functioning glucocorticoid receptors. Because steroid resistance is a frequent complication during chemotherapy, changes in lipid composition in membranes of neoplastic lymphoid cells might be a factor in the development of glucocorticoid-induced phenotypic alterations that do not directly involve the receptor system. The hypothesis which will be tested in the course of this study is formulated around the assumption that steroid induced lipid changes increase influx of ionic calcium into the cells thus stimulating the calcium-dependent endonuclease leading to nuclear fragmentation. The methodology to be used in this project will involve cholesterol and dolichol analyses by HPLC combined with radioisotope labeling studies of DNA fragmentation and measurement of Ca2+ influx by means of fluorescent probe Fura 2. Besides its importance in elucidating the mechanism of resistance to glucocorticoids, this study is also relevant to the role of lipid synthesis in the retroviral infection of lymphoid cells including infections caused by HIV.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA008315-26
Application #
3163302
Study Section
Pathology B Study Section (PTHB)
Project Start
1985-05-01
Project End
1992-04-30
Budget Start
1990-05-01
Budget End
1991-04-30
Support Year
26
Fiscal Year
1990
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
Lee, Seung-Cheol; Marzec, Michal; Liu, Xiaobin et al. (2013) Decreased lactate concentration and glycolytic enzyme expression reflect inhibition of mTOR signal transduction pathway in B-cell lymphoma. NMR Biomed 26:106-14
Magnitsky, S; Belka, G K; Sterner, C et al. (2013) Lactate detection in inducible and orthotopic Her2/neu mammary gland tumours in mouse models. NMR Biomed 26:35-42
Magnitsky, S; Roesch, A; Herlyn, M et al. (2011) In vivo and ex vivo MR imaging of slowly cycling melanoma cells. Magn Reson Med 66:1362-73
Haug, J S; Goldner, C M; Yazlovitskaya, E M et al. (1994) Directed cell killing (apoptosis) in human lymphoblastoid cells incubated in the presence of farnesol: effect of phosphatidylcholine. Biochim Biophys Acta 1223:133-40
Bondar, O P; Melnykovych, G; Rowe, E S (1994) Effects of farnesol on the thermotropic behavior of dimyristoylphosphatidylcholine. Chem Phys Lipids 74:93-8
Voziyan, P A; Goldner, C M; Melnykovych, G (1993) Farnesol inhibits phosphatidylcholine biosynthesis in cultured cells by decreasing cholinephosphotransferase activity. Biochem J 295 ( Pt 3):757-62
Melnykovych, G; Haug, J S; Goldner, C M (1992) Growth inhibition of leukemia cell line CEM-C1 by farnesol: effects of phosphatidylcholine and diacylglycerol. Biochem Biophys Res Commun 186:543-8
Bansal, N; Nyquist, D A; Melnykovych, G (1992) Protein-linked isoprenoid lipids in dexamethasone-treated human lymphoid lines in culture. Biochem Cell Biol 70:489-95
Nyguist, D A; Watanabe, I; Melnykovych, G (1992) Alkyllysophospholipid influenced melanoma cell morphology is associated with decreased attachment to basement membrane. Ukr Biokhim Zh 64:76-85
Bansal, N; Houle, A G; Melnykovych, G (1990) Dexamethasone-induced killing of neoplastic cells of lymphoid derivation: lack of early calcium involvement. J Cell Physiol 143:105-9

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