Modulation of MDR‐1 expression by a H‐ras oncogene in a human colon carcinoma cell line

Abstract

In an established colon differentiation model, introduction of a c-H-ras-1 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 shown to accompany ras-related differentiation events resulting in decreased Pgp synthesis and a significant reduction in membrane Pgp as detected by immunoprecipitation, Western-blot and FACS analysis. Consistent with these observations was a reduction in Pgp-mediated drug resistance associated with Clone-A ras transfectants, with no alteration in drug sensitivity being observed with non-MDR drugs in these cells. An alternative differentiation model involves exposure of Clone-A cells to sodium butyrate. Under these conditions, differentiation-related changes 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 shows that modulation of Pgp expression in colon differentiation is dependent upon the differentiation induction agent used.

Correlation of Induction of ATP Binding Cassette Transporter A5 (ABCA5) and ABCB1 mRNAs with Differentiation State of Human Colon Tumor

“…The introduction of a c-H-ras-1 oncogene into a poorly differentiated human colon carcinoma cells has been reported to result in significant reduction of ABCB1 mRNA expression and P-glycoprotein-mediated drug resistance in association with acquisition of a more differentiated phenotype. 13) This suggested that the change in the expression profile of ABC transporters might be related to the properties of the tumors in each differentiation stage. One possible function of ABCA5 in tumors would be as a drug efflux transporter, which might result in multi-drug resistance, in association with ABCB1.…”

Microvillar cell surface as a natural defense system against xenobiotics: a new interpretation of multidrug resistance

“…Growing multicellular prostate tumor spheroids develop quiescent cell subpopulations in central regions with features of intrinsic multicell-mediated drug resistance (117,118). MDR is a constitutional property of differentiated hepatocytes (70) and epithelial cells (54,91). Expression of P-glycoprotein is positively correlated with differentiation in tumor cells (10,48,54,91).…”

“…MDR is a constitutional property of differentiated hepatocytes (70) and epithelial cells (54,91). Expression of P-glycoprotein is positively correlated with differentiation in tumor cells (10,48,54,91). Reduced growth rate and decreased tumorigenicity correlate with a high level of MDR in many cell lines (8).…”

Oncogenic Ras downregulatesmdr1bexpression through generation of reactive oxygen species

“…Therefore, it is possible that oncogenic Ras could up-regulate mdr1b gene expression. However, others have suggested that an oncogenic Ras transformation had no effect on mdr-1 gene expression [9] and H-Ras expression led to the downregulation of mdr-1 gene expression in human colon carcinoma and acute myeloid leukemia cells [10,11]. In this study, we tries to determine the relationship between dominant active H-Ras and mdr1b expression.…”

“…Several studies have reported that active Ras causes MDR1 expression and leads to anticancer drug resistance [6][7][8]. However, others have found that Ras activation was not able to up-regulate the Jun S et al MDR1 gene [9], and that oncogenic Ras overexpression resulted in the downregulation of MDR1 expression and a subsequent reduction in surface-localized Pgp [10,11].…”