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Influence of exogenous RAR alpha gene on MDR1 expression and P-glycoprotein function in human and rodent cell lines
T P Stromskaya1, E Y Rybalkina, A A Shtil
1Cancer Research Center of Russian Academy of Medical Sciences, Moscow.
Abstract:
The goal of our study was to obtain direct evidence of co-ordinated regulation of P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) and differentiation in tumour cells and to study some signalling pathways involved in joint regulation of these two cell phenotypes. The sublines of human melanoma (mS) and hepatoma (human HepG2 and rat McA RH 7777) cell lines were obtained by retroviral infection of the wild-type cells with the cDNA of the human retinoic acid receptor alpha (RAR alpha). The resulting sublines stably overexpressed exogenous RAR alpha gene. The infectants became more differentiated than the parental cells as determined by a decrease in the synthesis of the embryo-specific alpha-fetoprotein in HepG2 and McA RH 7777 hepatoma cells and by an increase in melanin synthesis in mS cells. The differentiation of human cells was accompanied by an increase in the amounts of MDR1 mRNA but not by an increase in P-gp activity as a drug transporter, in contrast, in the rat RAR alpha overexpressing cells P-gp functional activity was elevated. Treatment with cytotoxic drug (colchicine) or retinoic acid (RA) resulted in a slight increase in P-gp activity in the parental and RAR alpha-infected melanoma cells, whereas the increase in P-gp function in the infected hepatoma cells (both human and rat) was very prominent. Thus, we provide new evidence that cell differentiation caused by the overexpression of the gene participating in the differentiation programme leads to overexpression of MDR1 gene and drug resistance and that this effect is tissue and species specific. These data imply that the activation of the RA-controlled signalling pathway up-regulates MDR1 gene expression.
Insights
Cell differentiation, induced by retinoic acid receptor alpha (RARα) overexpression, upregulates multidrug resistance (MDR) gene expression. This effect on P-glycoprotein (P-gp) activity is tissue and species-specific, impacting drug resistance.
Area of Science:
- Molecular Biology
- Cell Biology
- Pharmacology
Background:
- Multidrug resistance (MDR) in tumors is a major challenge in cancer therapy.
- P-glycoprotein (P-gp) is a key transporter involved in MDR.
- Coordinated regulation of MDR and cell differentiation is not fully understood.
Purpose of the Study:
- To investigate the direct evidence of coordinated regulation between P-gp-mediated MDR and cell differentiation.
- To explore signaling pathways involved in the joint regulation of these cellular phenotypes.
- To determine the tissue and species-specific effects of retinoic acid receptor alpha (RARα) on MDR and differentiation.
Main Methods:
- Retroviral infection of human melanoma (mS) and hepatoma (HepG2) and rat hepatoma (McA RH 7777) cell lines with human RARα cDNA.
- Assessment of cell differentiation by measuring alpha-fetoprotein synthesis (hepatoma cells) and melanin synthesis (melanoma cells).
- Quantification of MDR1 mRNA levels and P-gp functional activity (drug transport) following RARα overexpression and treatment with cytotoxic drugs or retinoic acid.
Main Results:
- RARα overexpression led to increased differentiation in all tested cell lines.
- Human cell differentiation increased MDR1 mRNA but not P-gp activity, while rat cells showed elevated P-gp activity.
- Treatment with colchicine or retinoic acid prominently increased P-gp function in RARα-overexpressing hepatoma cells.
Conclusions:
- Cell differentiation, driven by RARα overexpression, induces MDR1 gene expression and drug resistance.
- The observed effects of RARα on P-gp activity and MDR are tissue and species-specific.
- Activation of the retinoic acid signaling pathway upregulates MDR1 gene expression, suggesting a link between differentiation and drug resistance mechanisms.
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