R. Kramer et al., MODULATION OF MDR-1 EXPRESSION BY A H-RAS ONCOGENE IN A HUMAN COLON-CARCINOMA CELL-LINE, International journal of cancer, 54(2), 1993, pp. 275-281
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.