Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:5.99.1.2 (topoisomerase)
 9,166 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Conditions, such as anoxia or glucose starvation, which induce the glucose-regulated set of stress proteins also lead to resistance to adriamycin (J. Shen, C. Hughes, C. Chao, J. Cai, C. Bartels, T. Gessner, and J. Subjeck, Proc. Natl. Acad. Sci. USA 84:3278-3282, 1987) and etoposide. We report here that chronic anoxia, glucose starvation, 2-deoxyglucose, the calcium ionophore A23187, glucosamine, ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA), and tunicamycin (all specific inducers of the glucose regulated system) lead to a rapid and selective depletion of topoisomerase II from isolated nuclei of Chinese hamster ovary cells. This effect precedes a decline in tritiated thymidine incorporation and a redistribution of cells from S into G1/G0. The depletion of the enzyme is not accompanied by a decline in mRNA levels. We have also examined the mutant Chinese hamster K12 cell line which is temperature sensitive for expression of glucose-regulated proteins. When nuclei were isolated from K12 cells incubated at the nonpermissive temperature, a loss of topoisomerase II was again observed in congruence with the expression of stress proteins and cellular resistance to etoposide. These changes were not obtained in parental Wg1A cells incubated at the same temperature. These studies indicate that topoisomerase II is highly sensitive to glucose-regulated stresses and that its depletion from the nucleus, with the associated changes in cell cycle parameters, may represent general characteristics of the glucose-regulated state. Since anoxia and glucose starvation can occur during tumor development, this pathway for expression of drug resistance may have clinical ramifications.
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PMID:Depletion of topoisomerase II in isolated nuclei during a glucose-regulated stress response. 255 89

Glucose-regulated proteins (GRPs) are induced in cells by a variety of stress conditions such as treatment with 2-deoxyglucose, glucosamine, or the calcium ionophore A23187. We found that resistance to topoisomerase II (topo II) inhibitors, VP-16 and adriamycin, was induced by these treatments in human colon cancer HT-29 cells. Similar VP-16 resistance occurred in human ovarian cancer A2780 and breast cancer MCF-7 cells. The VP-16 resistance was reversible, since the sensitivity of the cells to VP-16 recovered within 24 h after the stresses were removed. Western blotting analysis showed that under these stress conditions the cellular contents of topo II alpha were decreased. The decreased expression of topo II was reversed to control levels within 24 h following removal of the stresses. The decrease in topo II levels under the stress conditions correlated well with the induction of GRP78 and 94. The close correlation between topo II and GRPs suggests that topo II is a protein sensitive to the glucose-regulated stresses. Since hypoxia and nutrient deprivation, which are also GRP-inducing conditions, could occur naturally in the solid tumors, the stress-associated cellular resistance through decrease in topo II levels may be a mechanism of the natural resistance of the solid tumors to topo II-directed chemotherapy.
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PMID:Glucose-regulated stresses confer resistance to VP-16 in human cancer cells through a decreased expression of DNA topoisomerase II. 870 75