Inhibition of glycogen phosphorylase (GP) by CP-91,149 induces growth inhibition correlating with brain GP expression.
The role of glycogenolysis in normal and cancer cells was investigated by inhibiting glycogen phosphorylase (GP) with the synthetic inhibitor CP-91,149. A549 non-small cell lung carcinoma (NSCLC) cells express solely the brain isozyme of GP, which was inhibited by CP-91,149 with an IC(50) of 0.5 microM. When treated with CP-91,149, A549 cells accumulated glycogen with associated growth retardation. Treated normal skin fibroblasts also accumulated glycogen with G1-cell cycle arrest that was associated with inhibition of cyclin E-CDK2 activity. Overall, cells expressing high levels of brain GP were growth inhibited by CP-91,149 correlating with glycogen accumulation whereas cells expressing low levels of brain GP were not affected by the drug. Analyses of 59 tumor cell lines represented in the NCI drug screen identified that every cell line expressed brain GP but the profile was dominated by a few highly GP expressing cell lines with lower than mean GP-a enzymatic activities. The correlation program, COMPARE, identified that the brain GP protein measured in the NCI cell lines corresponded with brain GP mRNA expression, ADP-ribosyltransferase 3, and colony stimulating factor 2 receptor alpha in the 10,000 gene microarray database with similar correlation coefficients. These results suggest that brain GP is present in proliferating cells and that high protein levels correspond with the ability of CP-91,149 to inhibit cell growth.
Schnier
Joachim B
JB
Department of Biological Chemistry, Tupper Hall, University of California School of Medicine, Davis, CA 95616, USA. jbschnier@ucdavis.edu
Nishi
Kayoko
K
Monks
Anne
A
Gorin
Fredric A
FA
Bradbury
E Morton
EM
D036002:ADP Ribose Transferases / Q000096:biosynthesis; D000465:Algorithms; D000577:Amides / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000201:enzymology* / Q000378:metabolism; D042846:CDC2-CDC28 Kinases; D002455:Cell Division / Q000187:drug effects*; D002478:Cells, Cultured; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D019992:Databases as Topic; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000378:metabolism; D005434:Flow Cytometry; D006003:Glycogen / Q000378:metabolism; D024981:Glycogen Phosphorylase / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D006801:Humans; D015151:Immunoblotting; D007211:Indoles / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D020411:Oligonucleotide Array Sequence Analysis; D020033:Protein Isoforms; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D016184:Receptors, Colony-Stimulating Factor / Q000096:biosynthesis; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured
D000577:Amides; C110844:CP 91149; D004791:Enzyme Inhibitors; D007211:Indoles; D020033:Protein Isoforms; D012333:RNA, Messenger; D016184:Receptors, Colony-Stimulating Factor; D006003:Glycogen; D024981:Glycogen Phosphorylase; D036002:ADP Ribose Transferases; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; C495892:Cdk2 protein, rat; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases