Tamoxifen reduces P-gp-mediated multidrug resistance via inhibiting the PI3K/Akt signaling pathway in ER-negative human gastric cancer cells

Mao, Zonglei; Zhou, Jin; Luan, Junwei; Sheng, Wei; Shen, Xinyong; Dong, Xiaoqiang

doi:10.1016/j.biopha.2013.10.003

Cited by 45 publications

(36 citation statements)

References 25 publications

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“…,21 Furthermore, phase II /III clinical trials have shown promising initial results of Effects of CAFs and IL-6 on IL-6/JAK/STAT3, PI3K/AKT and MAPK pathways. (a and b) Western blot analysis of lysates from MCF7 and T47D cells treated with IL-6 (20 ng/ml) (a) or CM from CAF18 (b), and treated with dimethyl sulfoxide (DMSO), or tamoxifen (1 μM), or tamoxifen (1 μM) combined with IL-6-neutralizing antibody (100 ng/ml), STAT3 inhibitor (10 μM), BEZ235 (1 μM) or BKM120 (1 μM) for 1 h using the indicated antibodies.…”

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confidence: 99%

IL-6 secreted by cancer-associated fibroblasts induces tamoxifen resistance in luminal breast cancer

et al. 2014

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Cancer-associated fibroblasts (CAFs) have been implicated in the development of resistance to anticancer drugs; however, the role and mechanism underlying CAFs in luminal breast cancer (BrCA) tamoxifen resistance are unclear. We found that stromal fibroblasts isolated from the central or peripheral area of BrCA have similar CAF phenotype and activity. In vitro and in vivo experiments showed that CAFs derived from clinical-luminal BrCAs induce tamoxifen resistance through decreasing estrogen receptor-α (ER-α) level when cultured with luminal BrCA cell lines MCF7 and T47D. CAFs promoted tamoxifen resistance through interleukin-6 (IL-6) secretion, which activates Janus kinase/signal transducers and activators of transcription (JAK/STAT3) and phosphatidylinositol 3-kinase (PI3K)/AKT pathways in tumor cells, followed by induction of epithelial-mesenchymal transition and upregulation of E3 ubiquitin ligase anaphase-promoting complex 10 activity, which targeted ER-α degradation through the ubiquitin-proteasome pathway. Inhibition of proteasome activity, IL-6 activity or either the JAK/STAT3 or PI3K/AKT pathways markedly reduced CAF-induced tamoxifen resistance. In xenograft experiments of CAFs mixed with MCF7 cells, CAF-specific IL-6 knockdown inhibited tumorigenesis and restored tamoxifen sensitivity. These findings indicate that CAFs mediate tamoxifen resistance through IL-6-induced degradation of ER-α in luminal BrCAs.Oncogene advance online publication, 9 June 2014; doi:10.1038/onc.2014.158.

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confidence: 99%

IL-6 secreted by cancer-associated fibroblasts induces tamoxifen resistance in luminal breast cancer

et al. 2014

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“…Recently, TAM showed broad-spectrum antitumor properties in ER − cancers, such as gastric cancer, colorectal cancer and cholangiocarcinoma [33]. In gastric cancer cells, TAM could inhibit the PI3K/Akt signaling pathway [7]. TAM could also decreased P-gp expression, to reverse multidrug resistance in QBC939/ADM cholangiocarcinoma cells [9].…”

Section: Discussionmentioning

confidence: 99%

“…Recently, TAM was shown to exert an antitumor effect in ER − cancers, including gastric cancer, colon cancer and cholangiocarcinoma [7–9]. Although the antitumor mechanism of TAM is considered to be competition with estrogen to block ER transcription, researchers have found a non-estrogen-dependent mechanism of TAM in ER − cancers by activating the apoptosis pathway to induce apoptosis.…”

Section: Introductionmentioning

confidence: 99%

Tamoxifen reverses epithelial–mesenchymal transition by demethylating miR-200c in triple-negative breast cancer cells

Wang

et al. 2017

BMC Cancer

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BackgroundAlthough the efficacy of tamoxifen (TAM) for breast cancer has been attributed to inducing cell cycle arrest and apoptosis by inhibiting estrogen receptor (ER) signaling, recent evidence indicates that TAM also possesses ER-independent antitumor activity through an unclear mechanism. The present study investigated the anti-tumor mechanism of TAM on mesenchymal triple-negative breast cancer (TNBC).MethodsThe inhibitory effect of TAM on tumor migration and metastasis was analyzed by transwell chamber in vitro and by murine xenograft model in vivo. The promoter sequence of miR-200c was predicted by an online CpG island predictor. Relative expression of miR-200c was measured by quantitative real-time PCR.ResultsAfter treatment with TAM, mesenchymal TNBC cells (MCF-7/ADR and MDA-MB-231) morphologically changed from mesenchymal to epithelial types. Meanwhile, cell migration ability was also significantly decreased in ER-positive breast cancer cells after exposure to TAM. Consistent with these in-vitro results, TAM significantly suppressed lung metastasis rate of mesenchymal TNBC cells in murine xenograft tumors. miRNA array analysis of two types of breast cancer cells showed that miR-200c expression was inhibited in mesenchymal TNBC cells, but increased after TAM treatment due to demethylation of miR-200c promoters.ConclusionsOur results indicate that TAM inhibits cell migration and enhances chemosensitivity of mesenchymal TNBC cells by reversing their EMT-like property; and that this EMT-reversal effect results from upregulation of miR-200c through demethylating its promoter. To our knowledge, this is the first explanation of a non-ER-related mechanism for the effect of TAM on mesenchymal TNBC cells.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-017-3457-4) contains supplementary material, which is available to authorized users.

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“…Activation of the PI3K/Akt pathway inhibits cell apoptosis by mediating the endogenous expression of Bcl-2 and Bax, which are mediators of apoptosis and are are the most frequently targeted genes regulating apoptosis in cells (36). In addition, activation of the PI3K/Akt pathway reduces the expression levels of P-gp, BCRP, MRP1 and other members of the ABC transporter superfamily (37)(38)(39)(40). These two aspects of the PI3K/Akt pathway, at least in part, induce the development of drug resistance.…”

Section: Discussionmentioning

confidence: 99%

Paclitaxel resistance in MCF-7/PTX cells is reversed by paeonol through suppression of the SET/phosphatidylinositol 3-kinase/Akt pathway

Zhang

Cai

Chen

et al. 2012

Molecular Medicine Reports

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Breast cancer is one of the most prevalent types of malignant tumor. Paclitaxel is widely used in the treatment of breast cancer; however, the major problem contributing to the failure of chemotherapy in breast cancer is the development of drug resistance. Therefore, it is necessary to identify novel therapeutic targets and reversal agents for breast cancer. In the present study, the protein expression levels of SET, protein phosphatase 2A (PP2A) and phosphatidylinositol 3-kinase (PI3K)/Akt pathway were determined in MCF-7/PTX human breast carcinoma paclitaxel-resistant cells using western blot analysis. Small interference RNAs (siRNAs) were used to knock down the gene expression of SET in MCF-7/PTX cells and the cell viability was assessed following treatment with paclitaxel, using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assays and flow cytometry. In addition, western blot analysis was used to determined PI3K/Akt pathway activity following SET knockdown. Furthermore, the reversal effects of paeonol on paclitaxel, and its underlying mechanisms of action, were investigated using western blot analysis and reverse transcription-quantitative polymerase chain reaction. The results demonstrated that increased levels of SET and PI3K/Akt pathway proteins were present in the MCF-7/PTX cells, compared with normal MCF-7 cells. Knockdown of SET significantly sensitized MCF-7/PTX cells to paclitaxel and induced cell apoptosis. In addition, the expression levels of the adenosine triphosphate binding cassette (ABC) transporter proteins were significantly reduced in the MCF-7/PTX cells compared with the normal MCF-7 cells. SET-induced paclitaxel resistance was found to be associated with the activation of the PI3K/Akt pathway. Paeonol significantly reduced the mRNA and protein expression levels of SET in the MCF-7/PTX cells. Furthermore, paeonol significantly sensitized the MCF-7/PTX to paclitaxel via regulation of ABC transporters, B cell lymphoma-2 (Bcl-2) and Bcl-2-associated X protein. In addition, paeonol inhibited SET-mediated paclitaxel resistance by attenuating PI3K/Akt pathway activity in the MCF-7/PTX cells. In conclusion, the results of the present study demonstrated that SET was associated with paclitaxel resistance in MCF-7/PTX cells, and that paeonol reversed paclitaxel resistance in MCF-7/PTX cells by downregulating the activity of the SET/PP2A/Akt pathway.

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Tamoxifen reduces P-gp-mediated multidrug resistance via inhibiting the PI3K/Akt signaling pathway in ER-negative human gastric cancer cells

Cited by 45 publications

References 25 publications

IL-6 secreted by cancer-associated fibroblasts induces tamoxifen resistance in luminal breast cancer

IL-6 secreted by cancer-associated fibroblasts induces tamoxifen resistance in luminal breast cancer

Tamoxifen reverses epithelial–mesenchymal transition by demethylating miR-200c in triple-negative breast cancer cells

Paclitaxel resistance in MCF-7/PTX cells is reversed by paeonol through suppression of the SET/phosphatidylinositol 3-kinase/Akt pathway

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