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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.

SUBMITTER: Wang L

PROVIDER: S-EPMC6365707 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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

Wang Lei L Lin Na N Li Yan Y

Oncology reports 20190111 3

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 ...[more]

PMID: 30664164

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Project description:BackgroundTriple-negative breast cancer (TNBC) is a malignant subtype of breast cancer, the main treatments for which are chemotherapy and surgery. PIK3CA is an oncogene that encodes the p110α subunit of class IA PI3K to regulate cell proliferation and apoptosis. Some reports have observed neoadjuvant chemotherapy (NAC) to have poor pathological complete response (pCR) rates in TNBC with PIK3CA mutation. This study aimed to explore the mechanism of how mutant PIK3CA alters chemotherapeutic susceptibility in TNBC.MethodsTNBC cell lines (MDA-MB-231 and MDA-MB-468) with PIK3CA gene mutations (E545K and H1047R regions) and overexpression were established by transfection. NOD/SCID mice were used for in vivo experiments. Epirubicin was used as the chemotherapeutic agent. Cell viability, cell cycle, apoptosis, and Transwell assays were conducted for phenotype analysis. Western blot, quantitative reverse transcription-polymerase chain reaction, and immunohistochemistry were used to detect gene and protein expression levels. A clinical analysis of 50 patients with TNBC was also performed.ResultsCell viability and Transwell assays showed that PIK3CA mutation promoted TNBC cell growth and conferred an enhanced migratory phenotype. Cell cycle and apoptosis assays showed that PIK3CA mutation moderately improved the proliferation ability of TNBC cells and remarkably inhibited their apoptosis. After epirubicin therapy, the proportion of early apoptotic cells decreased among cells with PIK3CA mutation. Further, xenograft tumors grew faster in NOD/SCID mice injected with mutated cell lines than in control group, suggesting that PIK3CA mutation caused chemotherapy resistance. Importantly, western blot and immunohistochemical analysis showed that cells and mouse tumors in the PIK3CA mutation groups exhibited different expression levels of apoptosis-related markers (Xiap, Bcl-2, and Caspase 3) and proteins associated with the PI3K/AKT/mTOR pathway (p110α, AKT, p-AKT, mTOR, p-mTOR, p-4E-BP1, p-p70S6K, and Pten). Moreover, prognostic analysis of 50 patients with TNBC indicated that PIK3CA mutation might be linked with relapse and death.ConclusionsPIK3CA mutation confers resistance to chemotherapy in TNBC by inhibiting apoptosis and activating the PI3K/AKT/mTOR signaling pathway.

Dataset Information

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

Publications

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

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