Molecular comparisons of acquired and native mitomycin C resistance in human colon carcinoma cells

Abstract

Acquired mitomycin C (MMC) resistant phenotype in the HCT 116 human colon carcinoma cell line is associated with an inability of the resistant cells to activate MMC (Cancer Res., 46 (1986) 3456). This report shows that the natively resistant human colon carcinoma cell line (HCT 116b), which had never been exposed to the drug, also exhibited a deficiency in MMC activation. The deficient activation of MMC in the natively resistant cells (like their acquired resistant counterpart) was circumvented by the MMC analog BMY28282 which was designed with a low quinone reduction potential and thus a greater ease of reductive activation. Interestingly, the development of acquired MMC resistance in the HCT 116 to a level of resistance similar to that of the natively resistant cells also resulted in several other molecular alterations that paralleled the molecular phenotype of the natively MMC resistant HCT 116b cells. These alterations included a significant increase in membrane Ricinus communis I binding carbohydrate moieties ( M r 80,000–92,000) and decrease in the expression of specific membrane antigens ( M r 55,000–57,000). The decrease in phosphorylation of specific nuclear phosphoproteins was also observed. This included a major nuclear phosphoprotein with approximate M r- and pI-values corresponding to 63,000 5.0 , and three groups of lower molecular weight phosphoproteins with approximate M r- and pI-values corresponding to 22,000 6.4 , 22,000 6.8 , and 22,000 7.4 The results of these studies suggested that similar resistant mechanism(s) might exist in these acquired and natively MMC resistant cell lines which possessed similar level of resistance to MMC.