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Down-Regulation of Topoisomerase II in CEM Cells Selected for Merbarone Resistance Is Associated with Reduced Expression of Sp3¹

Division of Developmental Therapeutics, Cancer Center, University of Illinois at Chicago, Chicago, Illinois 60607-7173

DNA topoisomerase II (topo II) is a target for many clinically useful anticancer drugs. However, a major concern in the use of these drugs is the development of resistance, often manifested by reduced drug accumulation or reduced topo II activity, due to mutant enzyme or the enzyme's decreased expression. To date, little is known of how the topo II is down-regulated in the resistant cells. In this study, using CEM cells selected for resistance to merbarone, we found that topo II RNA levels were reduced, compared to the parental cells, and this corresponded to reduced protein levels, whereas there was no significant difference in the RNA stability among these cell lines. Furthermore, we detected a lower level of topo II promoter activity in these resistant cells compared to the drug-sensitive parents. Thus, the down-regulation of topo II appeared to occur at the transcriptional level. Nucleotide sequencing of the topo II promoter regions up to -1200 bp revealed no mutations, suggesting that some trans-acting factors are possibly involved in this down-regulation of topo II. In this context, we found by Northern blot analysis that the transcription factor, sp3, was reduced in the drug-resistant cell lines compared to the parental cells. Furthermore, cotransfection experiments revealed that Sp3 induced topo II promoter activity in a dose-dependent manner in drug-sensitive CEM cells, but its induction of topo II promoter activity was attenuated in the resistant B12 cells. Our results suggest that down-regulation of Sp3 might contribute to the reduced expression of topo II in certain drug-resistant tumor cells.

¹ This work was supported in part by research Grants CA40570 and CA30103 from the National Cancer Institute, NIH, Department of Health and Human Services (Bethesda, MD) and in part by the Cancer Center, University of Illinois at Chicago.

² To whom requests for reprints should be addressed, at Cancer Center (M/C569), University of Illinois at Chicago, 900 South Ashland Avenue, Chicago, IL 60607-7173. Phone: (312) 355-0827; Fax: (312) 355-0194; E-mail: wtbeck@uic.edu.

Received 6/10/97. Accepted 10/ 2/97.

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