scholarly journals Nuclear receptor 4A1 as a drug target for breast cancer chemotherapy

2015 ◽  
Vol 22 (5) ◽  
pp. 831-840 ◽  
Author(s):  
Erik Hedrick ◽  
Syng-Ook Lee ◽  
Ravi Doddapaneni ◽  
Mandip Singh ◽  
Stephen Safe
Keyword(s):  
Breast Cancer ◽  
Cell Proliferation ◽  
Cancer Cells ◽  
Cell Lines ◽  
Nuclear Receptor ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Breast Cancer Cells ◽  
Induced Apoptosis ◽  
Mcf 7

The orphan nuclear receptor 4A1 (NR4A1) is overexpressed in mammary tumors and breast cancer cell lines. The functional activity of this receptor was investigated by RNA interference with oligonucleotides targeted to NR4A1 (siNR4A1) and by treatment with NR4A1 antagonists. Breast cancer cells were treated with NR4A1 antagonists or transfected with siNR4A. Effects on cell proliferation and apoptosis as well as specific genes associated with these responses were investigated in MCF-7, SKBR3, and MDA-MB-231 cells, and in athymic nude mice bearing MDA-MB-231 cells as xenografts. Transfection of MCF-7, MDA-MB-231, and SKBR3 breast cancer cells with siNR4A1 decreased cell proliferation and induced apoptosis in these cell lines. Transfection of breast cancer cells with siNR4A1 also decreased expression of Sp-regulated genes includingsurvivin,bcl-2, and epidermal growth factor receptor, inhibited mTOR signaling in MCF-7 cells that express WT p53, and activated oxidative and endoplasmic reticulum stress through downregulation of thioredoxin domain-containing 5 and isocitrate dehydrogenase 1. 1,1-Bis(3′-indolyl)-1-(p-substituted phenyl)methanes (C-DIMs) are NR4A1 ligands that act as NR4A1 antagonists. Treatment with selected analogs also inhibited breast cancer cell and tumor growth and induced apoptosis. The effects of C-DIM/NR4A1 antagonists were comparable to those observed after NR4A1 knockdown. Results with siNR4A1 or C-DIMs/NR4A1 antagonists in breast cancer cells and tumors were similar to those previously reported in pancreatic, lung, and colon cancer cells. They demonstrate the potential clinical applications of NR4A1 antagonists in patients with tumors that overexpress this receptor.

scholarly journals Highly expressed SLCO1B3 inhibits the occurrence and development of breast cancer and can be used as a clinical indicator of prognosis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Tiantian Tang ◽  
Guiying Wang ◽  
Sihua Liu ◽  
Zhaoxue Zhang ◽  
Chen Liu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Proliferation ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Breast Cancer Cells ◽  
Migration And Invasion ◽  
Breast Cancer Cell Lines

AbstractThe role of organic anion transporting polypeptide 1B3 (SLCO1B3) in breast cancer is still controversial. The clinical immunohistochemical results showed that a greater proportion of patients with negative lymph nodes, AJCC stage I, and histological grade 1 (P < 0.05) was positively correlated with stronger expression of SLCO1B3, and DFS and OS were also increased significantly in these patients (P = 0.041, P = 0.001). Further subgroup analysis showed that DFS and OS were significantly enhanced with the increased expression of SLCO1B3 in the ER positive subgroup. The cellular function assay showed that the ability of cell proliferation, migration and invasion was significantly enhanced after knockdown of SLCO1B3 expression in breast cancer cell lines. In contrast, the ability of cell proliferation, migration and invasion was significantly reduced after overexpress the SLCO1B3 in breast cancer cell lines (P < 0.05). Overexpression or knockdown of SLCO1B3 had no effect on the apoptotic ability of breast cancer cells. High level of SLCO1B3 expression can inhibit the proliferation, invasion and migration of breast cancer cells, leading to better prognosis of patients. The role of SLCO1B3 in breast cancer may be related to estrogen. SLCO1B3 will become a potential biomarker for breast cancer diagnosis and prognosis assessment.

scholarly journals Characterising the Response of Human Breast Cancer Cells to Polyamine Modulation

Biomolecules ◽  
2021 ◽  
Vol 11 (5) ◽  
pp. 743
Author(s):  
Oluwaseun Akinyele ◽  
Heather M. Wallace
Keyword(s):  
Breast Cancer ◽  
Cell Proliferation ◽  
Cell Growth ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Breast Cancer Cells ◽  
Growth Responses ◽  
Cancer Management ◽  
Mcf 7

Breast cancer is a complex heterogeneous disease with multiple underlying causes. The polyamines putrescine, spermidine, and spermine are polycationic molecules essential for cell proliferation. Their biosynthesis is upregulated in breast cancer and they contribute to disease progression. While elevated polyamines are linked to breast cancer cell proliferation, there is little evidence to suggest breast cancer cells of different hormone receptor status are equally dependent on polyamines. In this study, we characterized the responses of two breast cancer cells, ER+ (oestrogen receptor positive) MCF-7 and ER- MDA-MB-231 cell lines, to polyamine modulation and determined the requirement of each polyamine for cancer cell growth. The cells were exposed to DFMO (a polyamine pathway inhibitor) at various concentrations under different conditions, after which several growth parameters were determined. Exposure of both cell lines to DFMO induced differential growth responses, MCF-7 cells showed greater sensitivity to polyamine pathway inhibition at various DFMO concentrations than the MDA-MB-231 cells. Analysis of intracellular DFMO after withdrawal from growth medium showed residual DFMO in the cells with concomitant decreases in polyamine content, ODC protein level, and cell growth. Addition of exogenous polyamines reversed the cell growth inhibition, and this growth recovery appears to be partly dependent on the spermidine content of the cell. Similarly, DFMO exposure inhibits the global translation state of the cells, with spermidine addition reversing the inhibition of translation in the breast cancer cells. Taken together, these data suggest that breast cancer cells are differentially sensitive to the antitumour effects of polyamine depletion, thus, targeting polyamine metabolism might be therapeutically beneficial in breast cancer management based on their subtype.

scholarly journals WD-3 inhibits the proliferation of breast cancer cells by regulating the glycolytic pathway

2020 ◽  
Author(s):  
Xiaodan Zhu ◽  
Lu Zhao ◽  
Jianliang You ◽  
Yiqun Ni ◽  
Zhipeng Wei ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Breast Cancer Cells ◽  
Cancer Cell Lines ◽  
Breast Cancer Cell Lines ◽  
Hexokinase 2 ◽  
Mcf 7

Number 3 Prescription (WD-3) is an herbal remedy used in traditional Chinese medicine that has been shown to improve the outcomes of patients with advanced colon and gastric cancers. This study aimed to investigate the effect of WD-3 on proliferation, glycolysis, and hexokinase 2 expression in breast cancer cells. Four breast cancer cell lines (MDA-MB-231, BT-549, MCF-7, and MCF-7/ADR-RES) were treated with different concentrations of WD-3 compared with blank control (phosphate-buffered saline). Each of the breast cancer cell lines was also divided into WD-3, paclitaxel, and blank control group. Cell proliferation and morphology were assessed by MTT assay, nuclear Hoechst 33258 staining, or immunofluorescence. Apoptosis was analyzed by flow cytometry. High performance liquid chromatography was used for measurement of ATP, ADP, and AMP. Hexokinase 2 expression was analyzed by Western blot and quantitative reverse transcription PCR. WD-3 inhibited proliferation and increased apoptosis in all four breast cancer cell lines, in a dose-dependent manner. ATP and EC (energy charge) were significantly decreased in WD-3-treated BT-549 and MDA-MB-231 cells. WD-3 significantly downregulated the protein and mRNA expression of hexokinase II in BT-549 cells, however, not in the other three breast cancer cell lines. Our findings indicate that WD-3 targets the glycolytic pathway in breast cancer cells to exert its antitumor activity.

Decrease in Cell Viability of Breast Cancer Cells by a Di-Hydroxylated Derivative of N-(2-hydroxyphenyl)-2-Propylpentanamide

2021 ◽  
Vol 21 ◽  
Author(s):  
Norma Lizeth Galindo-Alvarez ◽  
Humberto L. Mendoza-Figueroa ◽  
Martha Cecilia Rosales-Hernández ◽  
Norbert Bakalara ◽  
José Correa-Basurto
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Proliferative Activity ◽  
Breast Cancer Cells ◽  
Breast Cancer Cell Lines ◽  
Hydroxyl Groups ◽  
Mcf 7

Background: A preliminary study of the biotransformation by cytochrome P450 enzymes (CYP) of N-(2-hydroxyphenyl)-2-propylpentanamide (HO-AAVPA), an HDAC inhibitor, led to the synthesis of two hydroxylated derivatives: N-(2,4-dihydroxyphenyl)-2-propylpentanamide (5a) and N-(2,5-dihydroxyphenyl)-2-propylpentanamide (5b). Objective: The study aims to evaluate the anti-proliferative activity of these di-hydroxylated derivatives in breast cancer cell lines. Methods: MTT assays were conducted in MCF-7 and MDA-MB-231 cell lines. Additionally, in silico studies were carried out to evaluate the affinity of these derivatives with the HDAC1 enzyme. Results: Results showed that only 5b possess an enhanced anti-proliferative effect in breast cancer cell lines MCF-7 and MDA-MB-231. Docking studies revealed that the presence of hydroxyl groups, as well as the position of the additional hydroxyl groups, could have an impact on HDAC1 affinity and could explain the lack of activity of compound 5a. Conclusion: A priori, these results hypothesize that anti-proliferative activity of 5b could be related to HDAC1 inhibition and thus anti-proliferative activity in breast cancer cells.

Soluble Inflammatory Mediators Proteinase-3 and Neutrophil Elastase Are Targeted by PR1-Specific Immunotherapy After Cellular Uptake and Cross Presentation of PR1 Peptide by Breast Cancer Cells

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2089-2089
Author(s):  
Gheath Alatrash ◽  
Elizabeth Mittendorf ◽  
Anna Sergeeva ◽  
Pariya Sukhumalchandra ◽  
Na Qiao ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Breast Cancer Cells ◽  
Cancer Cell Lines ◽  
Breast Cancer Cell Lines ◽  
Cross Presentation ◽  
Mcf 7

Abstract Abstract 2089 The human leukocyte antigen (HLA)-A2 restricted nonapeptide PR1 (VLQELNVTV) was shown to be immunogenic in leukemia. A phase I/II clinical trial has been initiated with PR1 peptide vaccine and to date has demonstrated clinical efficacy, including complete remission and immunologic responses in patients with acute (AML) and chronic (CML) myeloid leukemia, as well as myelodysplastic syndrome. PR1 is derived from the serine proteases proteinase-3 (P3) and neutrophil elastase (NE), which are normally found within neutrophil azurophil granules and are released into the inflammatory milieu. We have shown that P3 and NE are taken up and cross presented by antigen presenting cells and that their cross presentation elicits PR1 immunity. Because P3 and NE are present in breast cancer biopsies, we hypothesized that P3/NE may be taken up by breast cancer cells and cross presented to PR1-CTL. We recently demonstrated that the breast cancer cell lines MDA-MB-231, MDA-MB-453, MCF-7 and HER18 do not endogenously express NE and that NE is taken up by these cell lines. In this report, using PCR, western blot and flow cytometry, we show that P3 also is NOT endogenously expressed by the breast cancer cell lines MDA-MB-231, MDA-MB-453, MCF-7 or HER18. Using confocal microscopy, we demonstrate that P3 is taken up by these breast cancer cell lines within 10 minutes of pulsing and localizes to LAMP-2 containing lysosomal vesicles by 4 hours, suggesting its processing for presentation by (HLA)-I (i.e. HLA-A2). Using 8F4, the novel PR1-HLA-A2 monoclonal antibody, we show that PR1 is cross presented from P3 by 3 of 4 HLA-A2+ breast cancer cell lines (MDA-MB-231, MDA-MB-453-A2+, MCF-7), and from NE by 1 of 4 breast cancer cell lines (MDA-MB-231). Next, we studied whether PR1 presentation made cells susceptible to PR1-specific killing by PR1-CTL and the 8F4 monoclonal antibody. We show that following 12-hour pulsing of the MDA-MB-231 cell line with NE or P3, PR1 CTLs killed up to 31% and 38% of the NE- or P3-pulsed breast cancer cells respectively, vs. <1% of ovalbumin (ova)-pulsed MDA-MB-231cells. Additionally, in a complement mediated cytotoxicity assay using 8F4 antibody, pulsing of MDA-MB-231 cells with P3 led to 60% cytotoxicity (vs. 40% in ova-pulsed cells). In conclusion, this study shows that 1) PR1 is cross presented by breast cancer cells following uptake of soluble P3 and NE and 2) PR1 expression makes breast cancer a target of PR1-specific immunotherapy. If uptake of P3 or NE, present in the inflammatory milieu of other solid tumors, also leads to PR1 cross presentation, then PR1-based immunotherapy may be useful to treat other non-hematopoietic tumors. These results support a new paradigm linking inflammation and innate immunity to adaptive immune responses to cancer. Disclosures: No relevant conflicts of interest to declare.

Effect of enzastaurin on cell signaling, proliferation and apoptosis in breast cancer cell lines

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 14121-14121
Author(s):  
B. Spankuch ◽  
E. Kurunci-Csacsko ◽  
T. Bauknecht ◽  
K. Strebhardt
Keyword(s):  
Breast Cancer ◽  
Cell Proliferation ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Breast Cancer Cells ◽  
Cancer Cell Lines ◽  
Breast Cancer Cell Lines ◽  
Caspase 9

14121 Background: Enzastaurin, an acyclic bisindolylmaleimide, is a potent selective serine/threonine kinase inhibitor that inhibits PKCβ, targets the PI3K/AKT pathway, and inhibits GSK3β phosphorylation. Enzastaurin induced apoptosis and decreased proliferation of various cancer lines, and decreased VEGF expression and microvessel density in human tumor xenografts. In animal models, enzastaurin had antitumor/antiangiogenic activity in non-small-cell lung, colon, renal cell, hepatocellular, and other cancers. Therefore, we sought to determine enzastaurin’s impact on cellular PKCβ-mediated signaling in breast cancer cells. Secondarily, we sought to determine the induction of the apoptotic cascade by enzastaurin. Methods: Breast cancer cell lines MCF-7, BT-474, MDA-MB-435 and SK-BR-3 were treated with differing enzastaurin concentrations. Western-Blot analyses were performed to examine PKCβ, phospho-GSK3β and caspase 9 expressions. The phenotype and proliferation of enzastaurin-treated cells were also monitored by fluorescence microscopy. Results: Treating all 4 cancer cell lines with ascending enzastaurin doses (0.1–10 μM) led to a significant downregulation of GSK3β phosphorylation (2–17%) compared to control cells. A 48–72 hr incubation with increasing enzastaurin doses also reduced the PKCβ expression significantly (5–50%). Moreover, a dose- dependent reduction of cell proliferation to levels of 15–40% compared to control cells with the highest enzastaurin concentration was detectable. We also saw a marked pro-caspase 9 reduction (0–30%) after enzastaurin compared to control cells. The microscopic inspection of treated cells phenotypically confirmed increasing apoptosis-induced cell death. Conclusions: Enzastaurin has a significant antiproliferative effect in different breast cancer cells. Moreover, enzastaurin suppresses GSK3β phosphorylation, suggesting that it may be a reliable pharmacodynamic marker for enzastaurin activity in breast cancer cells; however, more preclinical analysis is needed. Our study provides evidence for enzastaurin’s potential to directly suppress breast cancer cell proliferation and to induce tumor cell death by apoptotic induction. No significant financial relationships to disclose.

scholarly journals Role of WISP-2/CCN5 in the Maintenance of a Differentiated and Noninvasive Phenotype in Human Breast Cancer Cells

2007 ◽  
Vol 28 (3) ◽  
pp. 1114-1123 ◽  
Author(s):  
Asmaà Fritah ◽  
Cécile Saucier ◽  
Olivier De Wever ◽  
Marc Bracke ◽  
Ivan Bièche ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Breast Cancer Cells ◽  
Cancer Cell Lines ◽  
Tissue Growth ◽  
Breast Cancer Cell Lines ◽  
Mcf 7

ABSTRACT WISP-2/CCN5 is an estrogen-regulated member of the “connective tissue growth factor/cysteine-rich 61/nephroblastoma overexpressed” (CCN) family of the cell growth and differentiation regulators. The WISP-2/CCN5 mRNA transcript is undetectable in normal human mammary cells, as well as in highly aggressive breast cancer cell lines, in contrast with its higher level in the breast cancer cell lines characterized by a more differentiated phenotype. We report here that knockdown of WISP-2/CCN5 by RNA interference in estrogen receptor alpha (ERα)-positive MCF-7 breast cancer cells induced an estradiol-independent growth linked to a loss of ERα expression and promoted epithelial-to-mesenchymal transdifferentiation. In contrast, forced expression of WISP-2/CCN5 directed MCF-7 cells toward a more differentiated phenotype. When introduced into the poorly differentiated, estrogen-independent, and invasive MDA-MB-231 breast cancer cells, WISP-2/CCN5 was able to reduce their proliferative and invasive phenotypes. In a series of ERα-positive tumor biopsies, we found a positive correlation between the expression of WISP-2/CCN5 and ID2, a transcriptional regulator of differentiation in normal and transformed breast cells. We propose that WISP-2/CCN5 is an important regulator involved in the maintenance of a differentiated phenotype in breast tumor epithelial cells and may play a role in tumor cell invasion and metastasis.

scholarly journals Interaction of Tumor Cells with the Hematopoietic Stem and Progenitor Cell Niche

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5139-5139 ◽  
Author(s):  
Abhishek Dhawan ◽  
Jens Friedrichs ◽  
Laura Bray ◽  
Lorenz C. Hofbauer ◽  
Manja Wobus ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Bone Marrow ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Breast Cancer Cells ◽  
Breast Cancer Cell Lines ◽  
Mcf 7

Abstract Introduction The bone marrow microenvironment regulates the self-renewal and differentiation of hematopoietic stem and progenitor cells (HSPCs), through a network dependent on cell-cell interaction. This interaction is mediated by morphogens, the extracellular matrix and cell adhesion molecules expressed and secreted by various cell types in the HSPC niche. Mesenchymal stromal cells (MSCs), as the major cellular component, maintain the stemness properties of the niche. The microenvironment thus becomes conducive for HSPCs to remain quiescent, thereby enabling long term self-renewal. Therefore, the safe haven in the bone marrow microenvironment and its constituent cell types can be targeted during tumorigenesis, thus making the niche neoplastic. Dissemination of breast cancer cells into the bone marrow has been described even in the early stages of the disease. The present study focuses on the influence of breast carcinomas on the genetic and functional profile of mesenchymal and hematopoietic progenitor cells of the bone marrow niche. Methods In vitro coculture models of breast cancer cell lines- MDA-MB231, MCF-7 and primary MSCs derived from the bone marrow of healthy donors were used in the study. Atomic- force microscopy based single-cell force spectroscopy (AFM-SCFS) and fluorescence based assays were used for cell adhesion experiments. Hydrogel based culture systems were used for 3-dimensional cocultures of breast cancer cells and MSCs. Hypoxic and normoxic culture conditions (0.5% and 20% oxygen respectively) were used for the experiments. Results The breast cancer cell lines caused a significant reduction in HSPC adhesion to MSCs (88% by MDA-MB 231 cells; p<0.005 and 73% by MCF-7 cells; p<0.005). AFM-SCFS studies also indicated a higher binding force between breast cancer cells and MSCs, as compared to HSPCs (MDA-MB231 cells-0.13nN, MCF-7 cells-0.074nN and HSPCs-0.05nN). MDA-MB231and MCF-7 cells express Intercellular adhesion molecule-1(ICAM-1), which has been shown to promote breast cancer metastasis (Hanlon et al, 2002; Rosette et al, 2005; Schröder C. et al, 2011). There was a significant difference in reduction of HSPC adhesion towards MSCs by ICAM-1 knockdown (ICAM-1 KD) tumor cells as compared to MDA-MB231 cells (84.83% by MDA-MB231 cells versus 28.11% by ICAM-1KD tumor cells, p<0.001). AFM-SCFS studies also showed a reduced binding force between ICAM-1 KD tumor cells and MSCs as compared to MDA-MB231cells (MDA-MB231 cells-0.14nN versus ICAM-1-KD tumor cells-0.05nN, p value<0.001). ICAM-1 KD studies thus showed that reduction in HSPC adhesion to MSCs by breast cancer cells was mediated through ICAM-1 signaling. A cytokine array was performed to investigate if breast cancer cell lines affect the cytokine profile of MSCs. The array showed altered expression of growth factors- Basic fibroblast growth factor (bFGF) and Platelet derived growth factor–beta (PDGF-BB) (2.2 fold upregulation and 0.5 fold downregulation in breast cancer cells- MSC cocultures respectively). Based on the array, a bFGF-mediated increase in the proliferation of MSCs and breast cancer cells in coculture was observed. The bFGF upregulation also caused an increased migration of MDA-MB231 cells towards MSCs in a transwell migration assay. An upregulation in the phosphorylation status of Akt was observed in breast cancer cells – MSC cocultures, as a downstream effect of upregulated bFGF levels. The bFGF-mediated increase in the proliferation of breast cancer cells and MSCs in coculture was shown to be dependent on the activation of PI3K-Akt pathway. The bFGF- mediated increase in the migration of MDA-MB231 cells towards MSCs was also inhibited upon addition of the PI3K blocker. Interestingly, the breast cancer cells caused a reduction in osteoblastic differentiation of MSCs by downregulation of PDGF-BB. Studies with 3-dimensional cocultures of breast cancer cells and MSCs also showed a reduction in osteoblastic differentiation of MSCs. Furthermore, long-term cocultures of breast cancer cells, HSPCs and MSCs showed reduced support for primitive HSPCs in the neoplastic niche. Conclusions These findings indicate a perturbed HSPC niche upon tumor invasion. The possible role of altered cytokine expression, consecutive downstream signaling in niche activation and bone turnover will be further studied using in vitro and in vivo approaches to recapitulate tumor micrometastases to the HSPC niche. Disclosures No relevant conflicts of interest to declare.

scholarly journals Effect of static magnetic field with quercetin and hesperetin on MCF-7 and MDA MB-231 breast cancer cells

2020 ◽  
Vol 0 (0) ◽  
Author(s):  
Gulsum Abusoglu ◽  
Bahadir Ozturk
Keyword(s):  
Breast Cancer ◽  
Magnetic Field ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Static Magnetic Field ◽  
Breast Cancer Cells ◽  
Breast Cancer Cell Lines ◽  
Mcf 7

AbstractObjectivesStatic magnetic field (SMF) was previously in practice for the therapy of some diseases and it has been thought that it may be a reliable supportive technique. The aim of this study was to find out the synergistic effect of SMF administration with flavonoids in terms of apoptosis on breast cancer cell lines.Material and methodsThe effects of flavonoids on the proliferation of breast cancer cell lines were observed by MTT cell viability test. The cells were treated with SMF + hesperetin and SMF + quercetin. Apoptosis rates and Bax, Bcl-2 protein levels were detected by flow cytometer and Western Blot, respectively.ResultsCell lines were treated with quercetin and quercetin + SMF, substantial amount of cells [3.96, 4.86, 11.40% for MCF-7 and MDA MB-231 cell lines, respectively (p<0.001)] were mainly in the apoptotic phase. The apoptosis rates of hesperetin and hesperetin + SMF were 2.53, 6.06, 10.10% (p<0.001) for MCF-7 and MDA MB-231 cell lines, respectively. Bax:Bcl-2 ratios were significantly increased after flavonoids + SMF exposure (2.7 vs. 1.6 fold (p<0.0001) in hesperetin + SMF group and 1.8 vs. 1.3-fold (p<0.0001) in quercetin + SMF group for MCF-7 and MDA MB-231 cell lines, respectively.ConclusionsSMF might support the anti-cancer properties of flavonoids, on breast cancer cells via mitochondria-related apoptosis pathway.

scholarly journals AKR1B10 promotes breast cancer cell proliferation and migration via the PI3K/AKT/NF-κB signaling pathway

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jiayao Qu ◽  
Jia Li ◽  
Yaming Zhang ◽  
Rongzhang He ◽  
Xiangting Liu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Proliferation ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Breast Cancer Cells ◽  
Migration And Invasion ◽  
Breast Cancer Cell Lines ◽  
Related Proteins ◽  
Mcf 7

Abstract Background Aberrant expression of Aldo-Keto reductase family 1 member B10 (AKR1B10) was associated with tumor size and metastasis of breast cancer in our published preliminary studies. However, little is known about the detailed function and underlying molecular mechanism of AKR1B10 in the pathological process of breast cancer. Methods The relationship between elevated AKR1B10 expression and the overall survival and disease-free survival of breast cancer patients was analyzed by Kaplan–Meier Plotter database. Breast cancer cell lines overexpressing AKR1B10 (MCF-7/AKR1B10) and breast cancer cell lines with knockdown of AKR1B10 (BT-20/shAKR1B10) were constructed to analyze the impact of AKR1B10 expression on cell proliferation and migration of breast cancer. The expression levels of AKR1B10 were detected and compared in the breast cancer cell lines and tissues by RT-qPCR, western blot and immunohistochemistry. The proliferation of breast cancer cells was monitored by CCK8 cell proliferation assay, and the migration and invasion of breast cancer cells was observed by cell scratch test and transwell assay. The proliferation- and EMT-related proteins including cyclinD1, c-myc, Survivin, Twist, SNAI1, SLUG, ZEB1, E-cadherin, PI3K, p-PI3K, AKT, p-AKT, IKBα, p-IKBα, NF-κB p65, p-NF-κB p65 were detected by western blot in breast cancer cells. MCF-7/AKR1B10 cells were treated with LY294002, a PI3K inhibitor, to consider the impact of AKR1B10 overexpression on the PI3K/AKT/NF-κB signal cascade and the presence of NF-κB p65 in nuclear. In vivo tumor xenograft experiments were used to observe the role of AKR1B10 in breast cancer growth in mice. Results AKR1B10 expression was significantly greater in breast cancer tissue compared to paired non-cancerous tissue. The expression of AKR1B10 positively correlated with lymph node metastasis, tumor size, Ki67 expression, and p53 expression, but inversely correlated with overall and disease-free survival rates. Gene Ontology analysis showed that AKR1B10 activity contributes to cell proliferation. Overexpression of AKR1B10 facilitated the proliferation of MCF-7 cells, and induced the migration and invasion of MCF-7 cells in vitro in association with induction of epithelial-mesenchymal transition (EMT). Conversely, knockdown of AKR1B10 inhibited these effects in BT-20 cells. Mechanistically, AKR1B10 activated PI3K, AKT, and NF-κB p65, and induced nuclear translocation of NF-κB p65, and expression of proliferation-related proteins including c-myc, cyclinD1, Survivin, and EMT-related proteins including ZEB1, SLUG, Twist, but downregulated E-cadherin expression in MCF-7 cells. AKR1B10 silencing reduced the phosphorylation of PI3K, AKT, and NF-κB p65, the nuclear translocation of NF-κB p65, and the expression of proliferation- and migration-related proteins in BT-20 cells. LY294002, a PI3K inhibitor, attenuated the phosphorylation of PI3K, AKT, and NF-κB p65, and the nuclear translocation of NF-κB p65. In vivo tumor xenograft experiments confirmed that AKR1B10 promoted breast cancer growth in mice. Conclusions AKR1B10 promotes the proliferation, migration and invasion of breast cancer cells via the PI3K/AKT/NF-κB signaling pathway and represents a novel prognostic indicator as well as a potential therapeutic target in breast cancer.

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