Abstract
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.
Highlights
Colorectal cancer is among the most common human malignancies and one of the leading causes of cancer deaths [1]
The colorectal cancer cell line Caco2 has previously been demonstrated to contain a subpopulation of cancer stem cell (CSC) with tumor initiating capacity characterized by expression of the CD133 and CD44 surface markers when grown in serum containing media [44]
Haraguchi et al reported that the CD133+ CD44+ population may be the real cancer initiating cells of human colorectal cancer [44] while Dalerba et al found that most CD44+ cells are CD133+, suggesting that CD44+ is an adequate marker for CSC in colorectal cancer [52]
Summary
Colorectal cancer is among the most common human malignancies and one of the leading causes of cancer deaths [1]. Despite the very encouraging results only a subset of colorectal cancer patients respond to the CPT-based therapies and problems with primary resistance or relapsed tumors remain a major problem [4,5,6,7]. The cytotoxicity of CPTs correlates directly with the intracellular activity of TopI and common mechanisms behind CPT resistance in cell lines include down-regulation of TopI activity [17,18,19,20,21,22,23] or mutations in the TOP1 gene leaving the enzyme insensitive towards CPT [4,24,25,26,27,28,29]. The importance of the cell-to-cell heterogeneity (intratumor heterogeneity) characteristic for most cancer cell populations for the occurrence of drug resistance is less well characterized [30,31]
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