Cell density-dependent regulation of mdr-1 gene expression in murine colon cancer cells

We studied the regulation of mdr-1 and P-glycoprotein in sparse and confluent cultures of murine CT-26 colon carcinoma cells. The expression level of mdr-1 mRNA transcripts (analyzed by Northern blot and in situ hybridization) and P-glycoprotein (analyzed by flow cytometry) inversely correlated with cell density. The modulation of mdr gene expression in sparse and confluent cells was not related to cell division, nutrient depletion, inhibition of protein synthesis, gap junction status, extracellular ATP, or the presence of various extracellular matrixes, but may be related to cell-density and cell-contact mediated changes in phosphatase activity. The confluence-mediated downmodulation of mdr-1 increased the chemosensitivity of the cells to several anticancer drugs commonly associated with an in vitro MDR phenotype by increasing the intracellular accumulation of the drugs. These data may explain some of the discrepancies in results obtained when analyzing mdr gene expression in tumors growing in vivo or in vitro, and why mdi expression in tumors is localized to the periphery of the lesions.