scholarly journals ROS Mediate xCT-Dependent Cell Death in Human Breast Cancer Cells under Glucose Deprivation

Cells ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 1598 ◽  
Author(s):  
Mei-Chun Chen ◽  
Li-Lin Hsu ◽  
Sheng-Fan Wang ◽  
Chih-Yi Hsu ◽  
Hsin-Chen Lee ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Death ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Breast Cancer Cells ◽  
Critical Role ◽  
Glucose Deprivation ◽  
Glutathione Biosynthesis ◽  
Dependent Cell ◽  
Amp Activated Protein Kinase

xCT, also known as solute carrier family 7 member 11 (SLC7A11), the light chain of the cystine/glutamate antiporter, is positively correlated with cancer progression due to antioxidant function. During glucose deprivation, the overexpression of xCT does not protect cancer cells but instead promotes cell death. Further understanding the mechanism of glucose deprivation-induced cell death is important for developing anticancer treatments targeting the glucose metabolism. In this study, we found that breast cancer cells with a high expression of xCT demonstrated increased levels of reactive oxygen species (ROS) and were more sensitive to glucose deprivation than the cells with a low expression of xCT. However, AMP-activated protein kinase (AMPK) did not significantly affect glucose-deprivation-induced cell death. The antioxidant N-acetyl-cysteine prevented glucose-deprivation-induced cell death, and the glutathione biosynthesis inhibitor L-buthionine-S, R-sulfoximine enhanced glucose-deprivation-induced cell death. The inhibition of xCT by sulfasalazine or a knockdown of xCT reduced the glucose-deprivation-increased ROS levels and glucose-deprivation-induced cell death. Glucose deprivation reduced the intracellular glutamate, and supplementation with α-ketoglutarate prevented the glucose-deprivation-increased ROS levels and rescued cell death. The knockdown of sirtuin-3 (SIRT3) further enhanced the ROS levels, and promoted xCT-related cell death after glucose deprivation. In conclusion, our results suggested that ROS play a critical role in xCT-dependent cell death in breast cancer cells under glucose deprivation.

scholarly journals Raloxifene Induces Autophagy-Dependent Cell Death in Breast Cancer Cells via the Activation of AMP-Activated Protein Kinase

2014 ◽  
Vol 38 (2) ◽  
pp. 138-144 ◽  
Author(s):  
Dong Eun Kim ◽  
Yunha Kim ◽  
Dong-Hyung Cho ◽  
Seong-Yun Jeong ◽  
Sung-Bae Kim ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Death ◽  
Protein Kinase ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Dependent Cell ◽  
Amp Activated Protein Kinase

Cxcl10 chemokine induces migration of ING4-deficient breast cancer cells via a novel crosstalk mechanism between the Cxcr3 and Egfr receptors

2021 ◽  
Author(s):  
Emily Tsutsumi ◽  
Jeremiah Stricklin ◽  
Emily A. Peterson ◽  
Joyce A. Schroeder ◽  
Suwon Kim
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Breast Cancer Cells ◽  
Critical Role ◽  
Disease Free Survival ◽  
Intact Cells ◽  
Free Survival ◽  
Egfr Receptors

The chemokine Cxcl10 has been associated with poor prognosis in breast cancer, but the mechanism is not well understood. Our previous study have shown that CXCL10 was repressed by the ING4 tumor suppressor, suggesting a potential inverse functional relationship. We thus investigated a role for Cxcl10 in the context of ING4 deficiencies in breast cancer. We first analyzed public gene expression datasets and found that patients with CXCL10 -high/ ING4 -low expressing tumors had significantly reduced disease-free survival in breast cancer. In vitro , Cxcl10 induced migration of ING4 -deleted breast cancer cells, but not of ING4 -intact cells. Using inhibitors, we found that Cxcl10-induced migration of ING4 -deleted cells required Cxcr3, Egfr, and the Gβγ subunits downstream of Cxcr3, but not Gαi. Immunofluorescent imaging showed that Cxcl10 induced early transient colocalization between Cxcr3 and Egfr in both ING4 -intact and ING4 -deleted cells, which recurred only in ING4 -deleted cells. A peptide agent that binds to the internal juxtamembrane domain of Egfr inhibited Cxcr3/Egfr colocalization and cell migration. Taken together, these results presented a novel mechanism of Cxcl10 that elicits migration of ING4 -deleted cells, in part by inducing a physical or proximal association between Cxcr3 and Egfr and signaling downstream via Gβγ. These results further indicated that ING4 plays a critical role in the regulation of Cxcl10 signaling that enables breast cancer progression.

scholarly journals Huaier Extract Inhibits Breast Cancer Progression Through a LncRNA-H19/MiR-675-5p Pathway

2017 ◽  
Vol 44 (2) ◽  
pp. 581-593 ◽  
Author(s):  
Jijun Wang ◽  
Xiaolong Wang ◽  
Tong Chen ◽  
Liyu Jiang ◽  
Qifeng Yang
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Breast Cancer Cells ◽  
Transfection Efficiency ◽  
Critical Role ◽  
Protein A ◽  
Flow Cytometric Analysis ◽  
Therapeutic Effects ◽  
Protein Levels

Background/Aims: Increasing evidence indicates that Huaier extract has promising therapeutic effects against cancer. However, the mechanisms that underlie its anti-tumor effects remain unclear. In recent years, various studies have shown that long noncoding RNAs (lncRNAs) play a critical role in the regulation of cancer development and progression. Here, we explored the role of lncRNAs in Huaier-induced tumor suppression. Methods: Microarray profiling was performed to identify the candidate lncRNAs affected by Huaier extract. Quantitative realtime PCR (qPCR) was used to evaluate the transfection efficiency and the influence of Huaier extract on H19 expression. The effect of Huaier extract on the cell viability was examined by MTT. Moreover, the rates of apoptotic cells were detected using flow-cytometric analysis. Western blot analysis was applied to show the protein levels of CBL. Results: Microarray data derived from Huaier-treated breast cancer cells identified H19 as a potential target. Huaier extract reduced the expression of H19. The over-expression of H19 inhibited the cytotoxic effects of Huaier extract; in contrast, reduced H19 expression enhanced the function of Huaier extract. MiR-675-5p was identified as a mature product of H19. Moreover, Huaier extract reduced the miR-675-5p expression. Upregulating miR-675-5p reversed the inhibitory effects of Huaier extract, whereas downregulating miR-675-5p sensitized breast cancer cells to the effect of Huaier extract. In addition, Huaier extract increased the expression of CBL protein, a direct target of miR-675-5p. Conclusion: Collectively, the data demonstrate that Huaier extract reduces viability and induces apoptosis in breast cancer cells via H19-miR-675-5p-CBL axis regulation.

scholarly journals Tumour suppressor OTUD3 induces growth inhibition and apoptosis by directly deubiquitinating and stabilizing p53 in invasive breast carcinoma cells

2020 ◽  
Author(s):  
Qian Pu ◽  
Yan-Rong Lv ◽  
Ke Dong ◽  
Wen-Wen Geng ◽  
Hai-Dong Gao
Keyword(s):  
Breast Cancer ◽  
Breast Carcinoma ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Breast Cancer Cells ◽  
Protein Modification ◽  
Critical Role ◽  
Ectopic Expression ◽  
Chemotherapy Drugs ◽  
Amino Terminal

Abstract Background P53 pathway inactivation plays an important role in the process of breast cancer tumourigenesis. Post-translational protein modification abnormalities have been confirmed to be an important mechanism underlying the inactivation of p53. Numerous deubiquitinating enzymes are aberrantly expressed in breast cancer, and a few deubiquitination enzymes are capable of deubiquitinating and stabilizing p53. Here, we report that OTUD3 is a deubiquitylase of p53 in breast carcinoma. Methods The correlation between the mRNA expression of OTUD3, TP53 and PTEN and the prognosis of BC was assessed with the Kaplan-Meier Plotter tool. OTUD3 protein expression in breast carcinoma was examined by immunohistochemistry and western blotting. The relationship among OTUD3, p53, and p21 proteins was analysed. Half-life analysis and ubiquitylation assay were performed to elucidate the molecular mechanism by which OTUD3 stabilizes p53. The interaction between OTUD3 and p53 in BC cells was verified by a co-immunoprecipitation assay and GST pulldown experiments. MTS proliferation detection, an apoptosis detection kit and colony formation asssy were used to investigate the functional effects of OTUD3 on breast cancer cells. Results OTUD3 downregulation is correlated with a poor prognosis in BC patients. OTUD3 expression is decreased in breast cancer tissues and independent of the histological grade.OTUD3 also inhibits cell proliferation and clone formation and increases the sensitivity of BC cells to apoptosis induced by chemotherapy drugs. A reduction in OTUD3 expression concomitant with decreased p53 abundance is correlated with human breast cancer progression. The ectopic expression of wild-type OTUD3, but not its catalytically inactive mutant, stabilizes and activates p53. Mechanistically, OTUD3 interacts directly with p53 through the amino-terminal OTU region. Finally, OTUD3 protects p53 from Mdm2-mediated ubiquitination and degradation, enabling the deubiquitination of p53 in BC cells. Conclusions In summary, we establish that OTUD3 is a potential therapeutic target for restoring p53 function in breast cancer cells and suggest that the OTUD3-p53 signalling axis plays a critical role in tumour suppression.

scholarly journals Glucose-dependent GPER1 expression modulates tamoxifen-induced IGFBP-1 accumulation

2019 ◽  
Vol 63 (2) ◽  
pp. 103-112 ◽  
Author(s):  
Yan Zheng ◽  
Kevin D Houston
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Breast Cancer Cells ◽  
Molecular Mechanisms ◽  
Glucose Deprivation ◽  
Amp Activated Protein Kinase ◽  
G Protein Coupled ◽  
In Cells

G protein-coupled estrogen receptor 1 (GPER1) is a seven-transmembrane receptor that mediates rapid cell signaling events stimulated by estrogens. While the role that GPER1 has in the modulation of E2-responsive tissues and cancers is well documented, the molecular mechanisms that regulate GPER1 expression are currently not well defined. The recently identified GPER1-dependent mechanism of tamoxifen action in breast cancer cells underscores the importance of identifying mechanisms that regulate GPER1 expression in this cell type. We hypothesized that GPER1 expression in breast cancer cells is sensitive to [D-glucose] and provide data showing increased GPER1 expression when cells were cultured in low [D-glucose]. To determine if the observed accumulation of GPER1 was AMP-activated protein kinase (AMPK)-dependent, small molecule stimulation or inhibition of AMPK was performed. AMPK inhibition decreased GPER1 accumulation in cells grown in low [D-glucose] while the AMPK-activating compound AICAR increased GPER1 accumulation in cells grown in high [D-glucose] media. Additionally, transfection of cells with a plasmid expressing constitutively active AMPK resulted in increased GPER1 accumulation. To determine if [D-glucose]-dependent GPER1 accumulation altered breast cancer cell response to tamoxifen, cells grown in the presence of decreasing [D-glucose] were co-treated with tamoxifen and IGFBP-1 transcription was measured. The results from these experiments reveal that D-glucose deprivation increased GPER1-mediated and tamoxifen-induced IGFBP-1 transcription suggesting that [D-glucose] may increase breast cancer cell sensitivity to tamoxifen. Taken together, these results identify a previously unknown mechanism that regulates GPER1 expression that modifies one aspect tamoxifen action in breast cancer cells.

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