GLUCOSE-REGULATED STRESSES CONFER RESISTANCE TO VP-16 IN HUMAN CANCER-CELLS THROUGH A DECREASED EXPRESSION OF DNA TOPOISOMERASE-II

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 topoisom erase II (topo II) inhibitors, VP-16 and adriamycin, was induced by th ese treatments in human colon cancer HT-29 cells. Similar VP-16 resist ance occurred in human ovarian cancer A2780 and breast cancer MCF-7 ce lls. 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 t he cellular contents of topo II alpha were decreased. The decreased ex pression of topo II was reversed to control levels within 24 h followi ng removal of the stresses. The decrease in topo II levels under the s tress conditions correlated well with the induction of GRP78 and 94. T he 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, coul d occur naturally in the solid tumors, the stress-associated cellular resistance through decrease in topo II levels may be a mechanism of th e natural resistance of the solid tumors to topo II-directed chemother apy.