Cancer cell resistance to chemotherapy is often associated with overexpression of plasma membrane ABC (ATP-binding cassette) pumps which transport a variety of compounds through the membrane against a concentration gradient by the ATP-dependent mechanism. Most of the ABC transporters, including first discovered P-glycoprotein (ABCB1) consist of two homologous halves each containing a transmembrane domain (TMD) involved in drug binding and efflux, and a cytosolic nucleotide-binding domain (NBD) involved in ATP binding and hydrolysis, with an overall (TMD-NBD)₂ domain topology. The ABC transporters constitute a large family of membrane proteins and have substrates of extremely divergent chemical structures, which include natural substances such as lipids, bile acids, peptides for antigen presentation and also exogenous and endogenous toxins (xenobiotics). By promoting active extrusion of these substrates outside cells, they reduce the body load of potentially harmful substances. However, they also eliminate various useful drugs from the body, causing multidrug resistance. It now appears that from many different ABC transporters characterized so far, only P-glycoprotein (ABCB1), MRP1 (ABCC1), MRP2 (ABCC2), and BCRP (ABCG2) are directly associated with the phenomenon of multidrug resistance observed in drug-resistant cell lines.

The human ABCG2 is a half-transporter and is postulated to form homodimers in the plasma membrane, which actively extrude a wide variety of chemically unrelated compounds from cells. Physiologically this protein plays a crucial role in protecting cells and tissues from toxic effects of xenobiotics, in particular in the intestine, liver and placenta, and is functionally involved in the blood-brain barrier. Overexpression of ABCG2 protein in many different tumor cell types has been shown to confer multidrug resistance to a variety of anticancer agents, including mitoxantrone, daunorubicin, doxorubicin, topotecan, methotrexate, flavopiridol and epirubicin. However, it has been established that the ABCG2 gene is characteristic for its very commonly occurring single nucleotide polymorphisms, which is associated with changed drug affinity and protein distribution, and single aminoacid substitutions in ABCG2 protein at position 482 greatly influence the substrate specificity of this transporter toward different xenobiotics.

More recent studies show that ABCG2 transporter plays a key role in the regulation and protection of stem cells, including a special type of cancer cells which also have the ability to self-renew and are called cancer initiating cells or cancer stem cells. One of the molecular markers associated with cancer initiating cell phenotype is increased expression of ABCG2 protein which could be one of the reasons of the inherent resistance of cancer initiating or cancer stem cells to antitumor treatment. The different functions of ABCG2 protein in drug resistance and the regulation of cancer stem cells will be discussed.

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