Related Experiment Videos
Expression of cytokeratin confers multiple drug resistance
P A Bauman1, W S Dalton, J M Anderson
1Department of Pharmacology and Toxicology, University of Arizona, Tucson 85724.
Abstract:
The cytokeratin network is an extensive filamentous structure in the cytoplasm whose biological function(s) is unknown. Based upon previous data showing the modification of cytokeratin by mitoxantrone, we investigated the ability of cytokeratin networks to influence the survival response of cells to chemotherapeutic agents. We have compared the survival of mouse L fibroblasts lacking cytokeratins with that of L cells transfected with cytokeratins 8 and 18 in the presence of chemotherapeutic drugs. The expression of cytokeratins 8 and 18 conferred a multiple drug resistance phenotype on cells exposed to mitoxantrone, doxorubicin, methotrexate, melphalan, Colcemid, and vincristine. The degree of drug resistance was 5-454 times that of parental cells, depending upon 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 resistance to ionizing radiation, which damages DNA independently of intracellular transport mechanisms. These data suggest a role for cytokeratin networks in conferring a drug resistance phenotype.
Insights
Cytokeratin networks influence cell survival against chemotherapy. Expressing cytokeratins 8 and 18 confers multiple drug resistance, suggesting a key role in cellular protection.
Area of Science:
- Cell Biology
- Biochemistry
- Molecular Oncology
Background:
- The biological functions of the extensive cytoplasmic cytokeratin network remain largely unknown.
- Previous research indicated cytokeratin modification by mitoxantrone, hinting at a potential role in drug response.
Purpose of the Study:
- To investigate the influence of cytokeratin networks on cellular survival in response to chemotherapeutic agents.
- To determine if cytokeratin expression confers drug resistance.
Main Methods:
- Comparison of survival rates between mouse L fibroblasts lacking cytokeratins and L cells expressing cytokeratins 8 and 18.
- Exposure of cell lines to various chemotherapeutic drugs (mitoxantrone, doxorubicin, methotrexate, melphalan, Colcemid, vincristine) and ionizing radiation.
Main Results:
- Cytokeratin 8 and 18 expression conferred a multiple drug resistance phenotype, with resistance increasing 5-454 fold compared to parental cells.
- This drug resistance was independent of altered growth characteristics, drug accumulation, or drug efflux.
- Cytokeratin did not confer resistance to ionizing radiation.
Conclusions:
- Cytokeratin networks play a significant role in conferring a drug resistance phenotype to cells.
- These findings suggest cytokeratins are involved in cellular defense mechanisms against chemotherapeutic agents.