Expression of ABCB1, ABCB5, and ABCG2 Transporters in Human Renal Cell Carcinoma and Their Underlying Signaling Pathways

Renal cell carcinoma (RCC) is frequently resistant to tyrosine kinase inhibitors (TKIs) such as sunitinib, limiting therapeutic efficacy. ATP-binding cassette (ABC) transporters, including ABCB1, ABCB5, and ABCG2, are important transporters implicated in multidrug resistance, influencing drug efflux and tumor progression. We aimed to evaluate the expression of ABCB1, ABCB5, and ABCG2 in human RCC tissues and human renal cancer cell lines CAKI-2 and A-498, and to investigate their potential association with sunitinib resistance and associated signaling pathways. Twenty paired tumorous and adjacent non-tumorous human kidney tissue samples were analyzed for ABC transporter gene expression using qRT-PCR. RCC cell lines CAKI-2 and A-498, including sunitinib-resistant derivatives, were treated with 40 µM sunitinib. The levels of transporters and key signaling proteins were assessed by Western blot. ABCG2 was consistently higher in tumorous tissues, and ABCB1 and ABCB5 showed grade-dependent increases in tumors. Resistant cells exhibited elevated ABCB1 and dynamic ABCB5 and ABCG2 expression patterns compared to sensitive cells, indicating an association between altered transporter expression and the resistant phenotype. Sunitinib treatment modulated signaling pathways, with differential activation of PI3K/Akt, NF-κB, and MAPK/ERK observed in sensitive versus resistant cells. Our findings suggest that altered ABCB1 and ABCG2 expression may be associated with the development of sunitinib resistance in RCC and may be linked to changes in key survival signaling pathways. These findings provide a basis for future functional studies investigating the role of ABC transporters in sunitinib resistance and may contribute to the development of personalized therapeutic strategies in RCC.