Cytokeratin expression results in a drug-resistant phenotype to six different chemotherapeutic agents.
The cytokeratin network is an abundant cytoplasmic system whose function is largely unknown. Recently, we have found that the introduction of a cytokeratin network into eukaryotic cells results in a drug resistance phenotype. The current study was undertaken to determine the universal nature of this phenomenon by investigating the survival response of two different cell lines to six different DNA-damaging agents using two different assays of cell survival. To correlate our in vitro assays of survival with known in vivo responses to DNA damage, we compared the apoptotic response of cytokeratin-positive and cytokeratin-negative cell lines. The results show that the introduction of a cytoskeletal network confers a resistant phenotype to mitoxantrone, doxorubicin, melphalan, bleomycin, and mitomycin C in the different cytokeratin-positive cell lines. No survival advantage was noted when damage was conferred by cisplatin or UV irradiation. We found the cytokeratin-positive cell lines were protected from apoptosis, while the cell lines without cytokeratins showed apoptosis in response to mitoxantrone exposure. Cytokeratin-dependent drug resistance is observed in different cell lines but is not observed with all DNA-damaging agents. The data suggest that the mechanism of this drug resistance may be attributed, in part, to a cytokeratin-conferred protection against apoptosis.
Anderson
J M
JM
Departments of Radiation Oncology, Pharmacology and Toxicology, Medicine, and Surgery, University of Arizona Cancer Center, Tucson, Arizona 85724, USA.
Heindl
L M
LM
Bauman
P A
PA
Ludi
C W
CW
Dalton
W S
WS
Cress
A E
AE
D016475:3T3 Cells; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D004247:DNA / Q000187:drug effects*; D004249:DNA Damage; D053938:DNA Fragmentation; D019008:Drug Resistance, Neoplasm; D007633:Keratins / Q000502:physiology*; D051379:Mice; D010641:Phenotype
D000970:Antineoplastic Agents; D007633:Keratins; D004247:DNA