Decreased camptothecin sensitivity of the stem-cell-like fraction of Caco2 cells correlates with an altered phosphorylation pattern of topoisomerase I

The CD44+ and CD44- subpopulations of the colorectal cancer cell line Caco2 were analyzed separately for their sensitivities to the antitumor drug camptothecin. CD44+ cells were less sensitive to camptothecin than CD44- cells. The relative resistance of CD44+ cells was correlated with (i) reduced ac...

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Published in:PloS one 2014-06, Vol.9 (6), p.e99628-e99628
Main Authors: Roy, Amit, Tesauro, Cinzia, Frøhlich, Rikke, Hede, Marianne S, Nielsen, Maria J, Kjeldsen, Eigil, Bonven, Bjarne, Stougaard, Magnus, Gromova, Irina, Knudsen, Birgitta R
Format: Article
Language:English
Subjects:
Antineoplastic Agents, Phytogenic - pharmacology
Biochemistry
Biology and life sciences
Caco-2 Cells
Camptothecin
Camptothecin - pharmacology
Cancer
Casein kinase II
CD44 antigen
Chemoresistance
Chemotherapy
Chromatography
Colorectal cancer
Colorectal carcinoma
Deoxyribonucleic acid
Dephosphorylation
DNA
DNA topoisomerase
DNA Topoisomerases, Type I - metabolism
Drug Resistance, Neoplasm
Enzymes
Genomes
Humans
Hyaluronan Receptors - metabolism
Kinases
Laboratories
Lymphoma
Medical research
Medicine and Health Sciences
Mimicry
Molecular biology
Neoplastic Stem Cells - drug effects
Phosphorylation
Phosphorylation - drug effects
Protein kinase C
Proteins
Sensitivity
Sensitivity analysis
Stem cells
Subpopulations
Tumors
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Summary:The CD44+ and CD44- subpopulations of the colorectal cancer cell line Caco2 were analyzed separately for their sensitivities to the antitumor drug camptothecin. CD44+ cells were less sensitive to camptothecin than CD44- cells. The relative resistance of CD44+ cells was correlated with (i) reduced activity of the nuclear enzyme topoisomerase I and (ii) insensitivity of this enzyme to camptothecin when analyzed in extracts. In contrast, topoisomerase I activity was higher in extracts from CD44- cells and the enzyme was camptothecin sensitive. Topoisomerase I from the two subpopulations were differentially phosphorylated in a manner that appeared to determine the drug sensitivity and activity of the enzyme. This finding was further supported by the fact that phosphorylation of topoisomerase I in CD44+ cell extract by protein kinase CK2 converted the enzyme to a camptothecin sensitive, more active form mimicking topoisomerase I in extracts from CD44- cells. Conversely, dephosphorylation of topoisomerase I in extracts from CD44- cells rendered the enzyme less active and camptothecin resistant. These findings add to our understanding of chemotherapy resistance in the Caco2 CD44+ cancer stem cell model.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0099628