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.

Ginsenoside Rp1, A Ginsenoside Derivative, Augments Anti-Cancer Effects of Actinomycin D via Downregulation of an AKT-SIRT1 Pathway

“…The PI3K/AKT pathway is often activated in cancer and contributes to tumorigenesis, metastasis, and chemoresistance [40,41]. Recently, PI3K/AKT signaling has been reported to modulate chemoresistance by regulating ABGG2 expression in human multiple myeloma [42]. In our study, ActD promoted SIRT1 upregulation as well as AKT phosphorylation ( Figure 5C).…”

PI3K/AKT pathway as a key link modulates the multidrug resistance of cancers

“…Upstream or downstream inhibition of epidermal growth factor receptor (EGFR/HERB)-dependent signaling regulates the AKT cascade and causes BCRP inhibition or activation. The PI3K/AKT signaling pathway regulated BCRP expression, and BCRP may protect multiple myeloma (MM) cells from the cytotoxicity of chemotherapeutic drugs by phosphatase and tensin homolog expression via a potential negative feedback loop of BCRP, and it is modulated by PTEN-mediated PI3K/AKT pathway regulation in NCI-H929 cells 121 . In addition, CSCs often exhibits a high ABCG2 transporter activity, the ratio of lateral cell (SP) cells in MM patients, ABCG2 expression and activation of the PI3K/AKT pathway are all positively correlated with disease progression.…”

Shikonin Enhances the Antitumor Effect of Cabazitaxel in Prostate Cancer Stem Cells and Reverses Cabazitaxel Resistance by Inhibiting the Expression of ABCG2 and ALDH3A1

“…Also, this pathway regulates the expression of ABCG2 and confers resistance to chemotherapy. The blockage of the PI3K/AKT pathway enhances the sensitivity to chemotherapeutic agents [49,50]. Therefore, we supposed that shikonin reversed the drug-resistant state through modulating the PI3K/AKT-ABCG2-ALDH3A1 axis in PCSCs.…”