Variable effects of sodium butyrate on the expression and function of the MDR1 (P-glycoprotein) gene in colon carcinoma cell lines
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T O Frommel1, J S Coon, T Tsuruo
1Department of Genetics, University of Illinois at Chicago 60612-7309.
Abstract:
Expression of the MDR1 (P-glycoprotein) gene confers resistance to several classes of chemotherapeutic drugs (multi-drug resistance). Colon carcinomas frequently express high levels of MDR1 mRNA and P-glycoprotein, presumably reflecting the origin of these tumors from MDR1-expressing normal colonic cells. In 4 colon carcinoma cell lines (SW 620, HCT-15, DLD-1, LS 180), MDR1 expression was reported in an earlier study to be elevated after exposure to a differentiating agent, sodium butyrate (NaB). In one of these cell lines (SW 620), increased MDR1 expression reportedly was not accompanied by a decrease in the accumulation or cytotoxicity of vinblastine, a P-glycoprotein-transported drug, suggesting a possible functional abnormality of NaB-induced P-glycoprotein. We have re-examined the effect of NaB on MDR1/P-glycoprotein expression and function in the same colon carcinoma cell lines. NaB treatment induced differentiation-related changes and increased expression of MDR1 mRNA in all 4 cell lines. A major increase in MDR1 mRNA and P-glycoprotein expression was observed in only one line, SW 620. This increase, however, was accompanied by a commensurate increase in the activity of P-glycoprotein, indicating that the induced protein was fully functional. NaB treatment caused a relatively minor increase in MDR1 mRNA expressed in the other 3 cell lines. Two of these lines showed a detectable increase in the P-glycoprotein expression and function, but in the third line (LS 180) P-glycoprotein was undetectable either before or after exposure to NaB. The magnitude of MDR1 induction by NaB showed no apparent correlation with differentiation-related changes induced by this agent.
Insights
Sodium butyrate (NaB) increases multi-drug resistance (MDR1) gene expression in colon cancer cells. Induced P-glycoprotein is functional, though expression levels vary, with one cell line showing no detectable P-glycoprotein.
Area of Science:
- Molecular Biology
- Cancer Research
- Cell Biology
Background:
- Multi-drug resistance (MDR1) gene expression, encoding P-glycoprotein, is crucial in chemotherapy resistance.
- Colon carcinomas often exhibit high MDR1 expression, potentially originating from normal colonic cells.
- Previous studies suggested potential functional abnormalities in NaB-induced P-glycoprotein in colon cancer cells.
Purpose of the Study:
- To re-examine the effect of sodium butyrate (NaB) on MDR1/P-glycoprotein expression and function in colon carcinoma cell lines.
- To clarify the functionality of NaB-induced P-glycoprotein in mediating drug resistance.
- To investigate the correlation between NaB-induced differentiation and MDR1 expression levels.
Main Methods:
- Treatment of four colon carcinoma cell lines (SW 620, HCT-15, DLD-1, LS 180) with sodium butyrate (NaB).
- Analysis of MDR1 mRNA expression levels.
- Assessment of P-glycoprotein expression and function.
- Evaluation of differentiation-related changes induced by NaB.
Main Results:
- NaB induced differentiation-related changes and increased MDR1 mRNA in all four cell lines.
- A significant increase in MDR1 mRNA and P-glycoprotein was observed in SW 620 cells, with fully functional P-glycoprotein.
- Other cell lines showed minor MDR1 mRNA increases; two had detectable P-glycoprotein function, while LS 180 had undetectable P-glycoprotein.
- No clear correlation was found between the magnitude of MDR1 induction and NaB-induced differentiation.
Conclusions:
- Sodium butyrate effectively induces MDR1 expression and P-glycoprotein in colon cancer cells, with the induced protein being functional.
- The extent of MDR1 induction and P-glycoprotein functionality varies significantly among different colon cancer cell lines.
- These findings highlight the complex regulation of MDR1 expression and P-glycoprotein function in colon carcinogenesis.