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Enhanced Expression of the DNA Topoisomerase II Gene in Response to Heat Shock Stress in Human Epidermoid Cancer KB Cells¹

Department of Biochemistry [K. M., K. K., S. S., T. U., H. T., M. K.], Oita Medical University, Hasama-machi, Oita 879-55; Laboratory of Anticancer Drug Research [Y. Y.], Original Compound R. & D. Operation Center, Taiho Pharmaceutical Co., Hanno-city, Saitama 357; and Department of Biochemistry [M. K.], Kyushu University School of Medicine, Maidashi, Fukuoka 812, Japan

Type II DNA topoisomerase breaks both DNA strands, and many anticancer agents including etoposide (VP-16) and teniposide (VM-26) have been developed by targeting topoisomerase II molecules. In this study we examined whether expression of the topoisomerase II gene is regulated in response to heat shock stress in human epidermoid cancer KB cells. Exposure of KB cells to 42°C for 3 to 24 h permitted cell growth at a slightly reduced rate but still at an exponential rate, in comparison with that at 37°C, whereas exposure to 45°C for 15 to 120 min caused the almost complete cessation of exponential growth. There appeared 5-fold or higher increases in mRNA levels of both topoisomerase II and a heat shock protein, hsp-70, after exposure to 42°C for 3 h, but only a slight, if any, increase in topoisomerase I mRNA. Nuclear run-on assays showed increased transcription of topoisomerase II and the hsp-70 gene after exposure to 42°C. By contrast, KB cells induced a rapid and transient increase of topoisomerase II mRNA after exposure to 45°C for 15 to 30 min, whereas the cellular level of hsp-70 mRNA was dramatically enhanced 60 min after exposure to 45°C. The immunoblot assay also demonstrated increased expression of topoisomerase II in KB cells exposed to 42°C. Decatenation activity of the nuclear extracts from KB cells was increased 1.5-fold by exposure to 42°C, but there appeared no increase in topoisomerase I activity. Prior exposure of KB cells to 42°C enhanced the cytotoxicity of VP-16, but not that of a topoisomerase I-targeting agent, a camptothecin analogue, CPT-11. However, exposure of KB cells to 42°C after treatment with VP-16 did not enhance the cytotoxicity induced by the drug. The formation of cleavable DNA-topoisomerase II-VP-16 complexes was also greatly increased by prior exposure to 42°C. Our present study proposes the hypothesis that the topoisomerase II gene might be one of the heat-shock-inducible genes and that hyperthermic anticancer therapy with topoisomerase II-targeting antitumor agents can be improved.

¹ This work was partly supported by grant-in-aid for cancer research funds from the Ministry of Education, Science, and Culture of Japan and also from the Ministry of Human Health and Welfare, Japan.

² To whom requests for reprints should be addressed, at Department of Biochemistry, Oita Medical University, Hasama-machi, Oita 879-55, Japan.

Received 8/10/92. Accepted 12/22/92.

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