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Increased Survival after Treatments with Anticancer Agents of Chinese Hamster Cells Expressing the Human M_r 27,000 Heat Shock Protein¹

Centre de recherche en cancérologie de l'Université Laval, L'Hôtel-Dieu de Québec, Québec, Canada G1R 2J6

A family of 10 thermoresistant cell lines cloned from Chinese hamster cells transfected with a plasmid containing the structural gene for the small human M_r 27,000 heat shock protein (HSP27) was used to assess the putative role of this heat shock protein in chemoresistance. These cells express varying amounts of human HSP27 in addition to the normal level of endogenous hamster HSP27. As previously observed in the case of thermoresistance, a significant positive linear correlation (P < 0.05) was found between cell survival in response to doxorubicin and the total amount of HSP27 expressed. Some clones were also examined for resistance to other drugs and chemicals. A statistically significant increased survival relative to the parental cells was observed following treatment with daunorubicin (three clones studied), colchicine, vincristine, actinomycin D, hydrogen peroxide, and sodium arsenite (one clone studied). However, the clone which expressed the highest level of HSP27 was as sensitive as control cells to the cytotoxic action of bis-chloronitrosourea and 5-fluorouracil. The relationship between HSP27 overexpression and increased resistance to cytotoxic agents was also evaluated in three independent pooled cell populations stably transformed with both the human HSP27 and the xanthine-guanine phosphoribosyltransferase gene and selected on the basis of resistance to mycophenolic acid and aminopterin. The results indicated that these cells survived significantly better than the control cells transfected with the marker gene only when exposed to doxorubicin. HSP27-mediated cellular protection was not associated either with decreased drug accumulation or with overexpression of P-glycoprotein. It is suggested that HSP27 might be involved in some form of chemoresistance and could participate in the development of clinical resistance to antineoplastic drugs.

¹ This work was supported by the Société de recherche sur le cancer and the Medical Research Council of Canada (Grant MT 7088).

² To whom requests for reprints should be addressed, at Centre de recherche en cancérologie de l'Université Laval, L'Hôtel-Dieu de Québec, 11 Côte du Palais, Québec, Canada G1R 2J6.

Received 11/20/90. Accepted 7/25/91.

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