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 IC50 of 0.5μM. 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 α 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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 126-134 |
| Number of pages | 9 |
| Journal | Biochemical and Biophysical Research Communications |
| Volume | 309 |
| Issue number | 1 |
| DOIs | |
| State | Published - Sep 12 2003 |
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Keywords
- Brain glycogen phosphorylase
- Cancer
- Cell cycle
- Colony stimulating factor α
- CP-91,149
- Glioma
- Tumor
ASJC Scopus subject areas
- Biochemistry
- Biophysics
- Molecular Biology
Cite this
Inhibition of glycogen phosphorylase (GP) by CP-91,149 induces growth inhibition correlating with brain GP expression. / Schnier, Joachim B.; Nishi, Kayoko; Monks, Anne; Gorin, Fredric A; Bradbury, E. Morton.
In: Biochemical and Biophysical Research Communications, Vol. 309, No. 1, 12.09.2003, p. 126-134.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Inhibition of glycogen phosphorylase (GP) by CP-91,149 induces growth inhibition correlating with brain GP expression
AU - Schnier, Joachim B.
AU - Nishi, Kayoko
AU - Monks, Anne
AU - Gorin, Fredric A
AU - Bradbury, E. Morton
PY - 2003/9/12
Y1 - 2003/9/12
N2 - 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 IC50 of 0.5μM. 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 α 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.
AB - 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 IC50 of 0.5μM. 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 α 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.
KW - Brain glycogen phosphorylase
KW - Cancer
KW - Cell cycle
KW - Colony stimulating factor α
KW - CP-91,149
KW - Glioma
KW - Tumor
UR - http://www.scopus.com/inward/record.url?scp=0041734885&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0041734885&partnerID=8YFLogxK
U2 - 10.1016/S0006-291X(03)01542-0
DO - 10.1016/S0006-291X(03)01542-0
M3 - Article
C2 - 12943673
AN - SCOPUS:0041734885
VL - 309
SP - 126
EP - 134
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
SN - 0006-291X
IS - 1
ER -