The role of hypoxia in expression of MDR-associated ABC transporters in embryonic stem cells
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| Year of publication | 2012 |
| Type | Appeared in Conference without Proceedings |
| MU Faculty or unit | |
| Citation | |
| Description | High level of ATP binding cassette (ABC)transporter expression is a typical feature of stem cells and many types of cancer stem cells. Multidrug resistance (MDR) of cancer cells is mainly caused by overexpression of ABC B1/ P-glycoprotein/MDR1, ABC C1/multidrug resistance-associated protein 1 (MRP1), and ABC G2/BCRP (Breast cancer resistance protein)(1). These transporters protect stem cells against toxic substances of either endogenous or exogenous origin. Moreover, they also have an important role in regulating the differentiation and proliferation of diverse cell types. Current data suggest that distribution of oxygen and nutrients is also involved in regulation of differentiation. Experiments with cultivation of different types of stem cells in vitro confirm the positive role of hypoxia in stemness maintenance (2). Stabilization of hypoxia-inducible factor (HIF) by hypoxia results in activation of this transcription factor for genes adapting the metabolism of cells to the lack of oxygen and simultaneously triggers the expression of growth factors that induce angiogenesis. In our experiments, we confirmed the expression of MDR transporters in mES cells by qRT-PCR. The highest expression showed ABC G2, which was previously proved to protects stem cells from oxidative stress (3). Functional analysis by flow cytometry also demonstrated the hight efflux activity of this transporter. Exposure of mES cells to hypoxia for 24 h resulted in decreased expression of the studied ABC transporters. This decrease can be explained by induction of cell differentiation as a result of low oxygen concentrations. The absence of HIF1 alpha did not reduce level of mRNA expression of MDR transporters and also lack of p38 kinase (kinase sensitive to reactive oxygen species (ROS) ? the key regulator of cellular response to oxidative stress) did not affect expression of MDR proteins. |
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