EXPRESSION OF CYTOKERATIN CONFERS MULTIPLE-DRUG RESISTANCE

The cytokeratin network is an extensive filamentous structure in the c ytoplasm whose biological function(s) is unknown. Based upon previous data showing the modification of cytokeratin by mitoxantrone, we inves tigated the ability of cytokeratin networks to influence the survival response of cells to chemotherapeutic agents. We have compared the sur vival of mouse L fibroblasts lacking cytokeratins with that of L cells transfected with cytokeratins 8 and 18 in the presence of chemotherap eutic drugs. The expression of cytokeratins 8 and 18 conferred a multi ple drug resistance phenotype on cells exposed to mitoxantrone, doxoru bicin, methotrexate, melphalan, Colcemid, and vincristine. The degree of drug resistance was 5-454 times that of parental cells, depending u pon the agent used. Drug resistance could not be attributed to altered growth characteristics, altered drug accumulation, or an altered drug efflux in the transfected cells. Cytokeratin does not confer resistan ce to ionizing radiation, which damages DNA independently of intracell ular transport mechanisms. These data suggest a role for cytokeratin n etworks in conferring a drug resistance phenotype.