REVERSIBLE TRANSCRIPTIONAL ACTIVATION OF MDR1 BY SODIUM-BUTYRATE TREATMENT OF HUMAN COLON-CANCER CELLS

We investigated the mechanism of sodium butyrate (NaB)-mediated induct ion of mdr1 mRNA in parental (wild type) and multidrug-resistant (Ad10 00) SW620 colon cancer cell lines. NaB treatment resulted in reversibl e, time-dependent increases in nuclear run-on transcription of endogen ous mdr1 in these cell lines that paralleled the reversible increases of mdr1 mRNA in both timing and magnitude. In contrast, NaB treatment had no effect on mdr1 mRNA stability. Thus, the effects of NaB on mdr1 mRNA levels are fully attributable to altered mdr1 transcription. Fur thermore, NaB induces the expression of transiently transfected chlora mphenicol acetyltransferase reporter plasmids that are under the trans criptional control of the mdr1 promoter (mdrCAT vectors). Transfection s using mdrCAT vectors modified by deletion and site-directed mutagene sis of the mdr1 promoter indicate that NaB-mediated induction of these vectors is at least partially dependent upon sequences present in the basal mdr1 promoter between -89 and +11 relative to the start site of transcription. The Y-box moth located between -82 and -73 contributes to NaB inducibility of mdrCAT vector expression in Ad1000 SW620 cells .