MODULATION OF MDR-1 EXPRESSION BY A H-RAS ONCOGENE IN A HUMAN COLON-CARCINOMA CELL-LINE

In an established colon differentiation model, introduction of a c-H-r as-I oncogene into a poorly differentiated human colon carcinoma cell line (Clone A) results in changes associated with the acquisition of a more differentiated phenotype. Down-regulation of mdr-1 mRNA was show n to accompany ras-related differentiation events resulting in decreas ed Pgp synthesis and a significant reduction in membrane Pgp as detect ed by immunoprecipitation, Western-blot and FACS analysis. Consistent with these observations was a reduction in Pgp-mediated drug resistanc e associated with Clone-A ras transfectants, with no alteration in dru g sensitivity being observed with non-MDR drugs in these cells. An alt ernative differentiation model involves exposure of Clone-A cells to s odium butyrate. Under these conditions, differentiation-related change s resulted in up-regulation of mdr-1 mRNA and Pgp synthesis, although no alteration in drug sensitivity was recorded. In agreement with this observation, the levels of membrane-associated Pgp remained unchanged throughout the period of exposure to sodium butyrate. This study show s that modulation of Pgp expression in colon differentiation is depend ent upon the differentiation induction agent used.