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Inhibition of glycogen phosphorylase (GP) by CP-91,149 induces growth inhibition correlating with brain GP expression
Joachim B Schnier1, Kayoko Nishi, Anne Monks
1Department of Biological Chemistry, Tupper Hall, University of California School of Medicine, Davis, CA 95616, USA. jbschnier@ucdavis.edu
Abstract:
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.
Insights
Inhibiting brain glycogen phosphorylase (GP) with CP-91,149 halts cancer cell growth and causes glycogen buildup. High brain GP levels in tumors correlate with drug sensitivity, suggesting a therapeutic target.
Area of Science:
- Biochemistry
- Cell Biology
- Oncology
Background:
- Glycogenolysis, the breakdown of glycogen, is a critical metabolic process.
- Glycogen phosphorylase (GP) is the rate-limiting enzyme in glycogenolysis.
- The role of brain GP in cancer cell proliferation is not fully understood.
Purpose of the Study:
- To investigate the role of glycogenolysis in normal and cancer cells.
- To determine the effect of inhibiting brain GP on cell growth and metabolism.
- To identify potential correlations between brain GP expression and drug sensitivity.
Main Methods:
- Utilized the synthetic GP inhibitor CP-91,149.
- Assessed the IC(50) of CP-91,149 in A549 non-small cell lung carcinoma (NSCLC) cells.
- Analyzed glycogen accumulation, cell cycle progression, and enzyme activity in treated cells.
- Examined brain GP expression across 59 tumor cell lines and correlated it with gene expression data.
Main Results:
- CP-91,149 effectively inhibited brain GP in A549 cells (IC(50) = 0.5 microM).
- Inhibition of brain GP led to glycogen accumulation and growth retardation in A549 cells.
- Normal fibroblasts treated with CP-91,149 showed glycogen accumulation and G1-cell cycle arrest.
- High brain GP protein levels in tumor cell lines correlated with growth inhibition by CP-91,149.
- Brain GP protein levels positively correlated with brain GP mRNA, ADP-ribosyltransferase 3, and colony stimulating factor 2 receptor alpha expression.
Conclusions:
- Brain GP is present in proliferating cells and its inhibition impacts cell growth.
- High levels of brain GP in cancer cells are associated with sensitivity to CP-91,149.
- Targeting brain GP may represent a viable therapeutic strategy for certain cancers.
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