The PI3K/AKT signaling pathway regulates ABCG2 expression and confers resistance to chemotherapy in human multiple myeloma

Abstract

Side population (SP) cells are involved in the development of multidrug resistance (MDR) in human multiple myeloma (MM), due to their cancer stem cell (CSC)-like phenotypes. ATP-binding cassette (ABC) drug transporter proteins have been reported to be closely associated with MDR in leukemia; however, the correlation between ABC proteins and the progression of MM remains unclear. The present study used MM cell lines and clinical samples to determine the role of ABC subfamily G member 2 (ABCG2) in MM via flow cytometry, reverse transcription-quantitative polymerase chain reaction and western blotting. SP cells sorted from MM cell lines, including NCI-H929 cells, via fluorescence-activated cell sorting, exhibited CSC-like phenotypes and expressed high levels of ABCG2. Expression of ABCG2 and activation of the phosphatidylinositol 3-kinase (PI3K)/AKT serine/threonine kinase (AKT) signaling pathway was positively associated with the proportion of SP cells in the NCI-H929 cell line. In addition, suppression of the PI3K/AKT pathway using LY294002 or rapamycin counteracted the protective effects of ABCG2 against chemotherapeutic drug treatment. Mechanistically, PI3K/AKT signaling may regulate ABCG2 expression, and ABCG2 may regulate phosphatase and tensin homolog expression via a potential negative feedback loop. Furthermore, SP cell proportion, ABCG2 expression and PI3K/AKT pathway activation were associated with disease progression in patients with MM. These findings indicated the critical roles of ABCG2 and PI3K/AKT signaling in controlling stemness of MM cells, and suggested a novel strategy for targeting ABCG2 and PI3K/AKT signaling to treat MM with MDR.