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Multidrug resistance (MDR) is a serious obstacle in breast cancer patients which limits chemotherapeutic drugs application. Our previous study confirmed that overexpression of nucleophosmin (NPM) was closely related to MDR in methotrexate-resistant breast cancer cells (MCF-7/MTX), and NPM could be a potential therapeutic target for chemoresistance. In this work, we aim to investigate NPM-mediated resistance mechanism in breast carcinoma. The NPM level was strongly positive in breast carcinoma tissues compared with adjacent normal samples, which was associated with lymph node metastasis. We found abnormal expression of NPM activated PI3K/Akt pathway and affected downstream apoptosis factors. Then, NPM level was attenuated by RNA interfering technology, the sensitivity of MCF-7/MTX cells to methotrexate was obviously increased, factor level of mitochondria apoptosis pathway was significantly augmented, and Akt phosphorylation was inhibited. Furthermore, examination of Akt and NPM level demonstrated that Akt inhibitor MK-2206 sensitised resistant cells to methotrexate and induced MCF-7/MTX cell apoptosis by PI3K/Akt pathway and mitochondria apoptosis pathway. These suggested NPM-induced resistance and anti-apoptosis were required for Akt activity. NPM has a crucial function in MDR of breast cancer through influencing Akt activity and resistant cell apoptosis, and it could be expected to become a therapeutic target for chemoresistance in breast cancer. [ABSTRACT FROM PUBLISHER]

Patient SE translation (SET) is a carcinogen in facilitating cellular growth and proliferation, and promoting tumorigenesis and metastasis. The present study was to investigate the resistance mechanisms associated with SET in paclitaxel-induced human breast cancer cells. The different expressions of SET, ATP-binding cassette (ABC) transporters and PI3K/Akt pathway between paclitaxel sensitive MCF-7/S and paclitaxel resistant MCF-7/PTX cells were identified using western blotting. We adopted plasmid transfection to upregulate SET in MCF-7/S cells and a novel SET antagonist COG112 to decrease SET in MCF-7/PTX cells. Subsequently, cell viability to paclitaxel was assessed by MTT assay and cell apoptosis was analyzed by flow cytometry. We found that levels of SET, ABC transporters and PI3K/Akt pathway were elevated in MCF-7/PTX. Upregulation of SET in MCF-7/S cells expressed resistant to paclitaxel and decreased cell apoptosis. Moreover, overexpression of SET promoted the mRNA and protein level of ABC transporters and PI3K/Akt signal pathway in MCF-7/S cells. Conversely, decreased level of SET by COG112 not only significantly sensitized MCF-7/PTX cells to paclitaxel, but also enhanced paclitaxel-induced cell apoptosis. Additionally, the levels of the ABC transporters and PI3K/Akt signal pathway were also reduced in the COG112-treated MCF-7/PTX cells. The above results demonstrated that SET was associated with paclitaxel resistance in MCF-7/PTX cells. [ABSTRACT FROM AUTHOR]