scholarly journals Triterpene Acid (3-O-p-Coumaroyltormentic Acid) Isolated From Aronia Extracts Inhibits Breast Cancer Stem Cell Formation through Downregulation of c-Myc Protein

2018 ◽  
Vol 19 (9) ◽  
pp. 2528 ◽  
Author(s):  
Hack Choi ◽  
Su-Lim Kim ◽  
Ji-Hyang Kim ◽  
Hong-Yuan Deng ◽  
Bong-Sik Yun ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Formation ◽  
Cancer Recurrence ◽  
Dependent Manner ◽  
New Paradigm ◽  
Triterpene Acid ◽  
Mammosphere Formation ◽  
Protein Levels ◽  
Survival Factor ◽  
Isolated Compound

Cancer stem cells (CSCs) are drug-resistant and radiation-resistant cancer cells that are responsible for tumor progression and maintenance, cancer recurrence, and metastasis. Targeting breast CSCs with phytochemicals is a new paradigm for cancer prevention and treatment. In this study, activity-guided fractionation from mammosphere formation inhibition assays, repeated chromatographic preparations over silica gel, preparatory thin layer chromatography, and HPLC using aronia extracts led to the isolation of one compound. Using 1H and 13C 2-dimensional nuclear magnetic resonance (NMR) as well as electrospray ionization (ESI) mass spectrometry, the isolated compound was identified as 3-O-p-coumaroyltormentic acid. This compound inhibits breast cancer cell proliferation and mammosphere formation in a dose-dependent manner and reduces the CD44high/CD24low subpopulation and aldehyde dehydrogenase (ALDH)-expressing cell population as well as the expression of the self-renewal-related genes CD44, SOX2, and OCT4. 3-O-p-Coumaroyltormentic acid preferentially reduced the protein levels of c-Myc, which is a CSC survival factor, by inducing c-Myc degradation. These findings indicate the novel utilization of 3-O-p-coumaroyltormentic acid for breast cancer therapy via disruption of c-Myc protein, which is a CSC survival factor.

scholarly journals Disruption of the NF-κB/IL-8 Signaling Axis by Sulconazole Inhibits Human Breast Cancer Stem Cell Formation

Cells ◽  
2019 ◽  
Vol 8 (9) ◽  
pp. 1007 ◽  
Author(s):  
Hack Sun Choi ◽  
Ji-Hyang Kim ◽  
Su-Lim Kim ◽  
Dong-Sun Lee
Keyword(s):  
Breast Cancer ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Cell Formation ◽  
Tumor Initiating Cells ◽  
Self Renewal ◽  
Mammosphere Formation ◽  
Protein Levels ◽  
New Findings ◽  
Poor Outcomes

Breast cancer stem cells (BCSCs) are tumor-initiating cells that possess the capacity for self-renewal. Cancer stem cells (CSCs) are responsible for poor outcomes caused by therapeutic resistance. In our study, we found that sulconazole—an antifungal medicine in the imidazole class—inhibited cell proliferation, tumor growth, and CSC formation. This compound also reduced the frequency of cells expressing CSC markers (CD44high/CD24low) as well as the expression of another CSC marker, aldehyde dehydrogenase (ALDH), and other self-renewal-related genes. Sulconazole inhibited mammosphere formation, reduced the protein level of nuclear NF-κB, and reduced extracellular IL-8 levels in mammospheres. Knocking down NF-κB expression using a p65-specific siRNA reduced CSC formation and secreted IL-8 levels in mammospheres. Sulconazole reduced nuclear NF-κB protein levels and secreted IL-8 levels in mammospheres. These new findings show that sulconazole blocks the NF-κB/IL-8 signaling pathway and CSC formation. NF-κB/IL-8 signaling is important for CSC formation and may be an important therapeutic target for BCSC treatment.

scholarly journals NQO1 is Required for β-Lapachone-Mediated Downregulation of Breast-Cancer Stem-Cell Activity

2018 ◽  
Vol 19 (12) ◽  
pp. 3813 ◽  
Author(s):  
Dong Kim ◽  
Je-Yoel Cho
Keyword(s):  
Breast Cancer ◽  
Stem Cells ◽  
Cell Proliferation ◽  
Stem Cell ◽  
Cancer Stem Cells ◽  
Cancer Stem Cell ◽  
Breast Cancer Stem Cell ◽  
Cancer Development ◽  
Dependent Manner ◽  
Mammosphere Formation

Cancer stem cells (CSCs) exhibit self-renewal activity and give rise to other cell types in tumors. Due to the infinite proliferative potential of CSCs, drugs targeting these cells are necessary to completely inhibit cancer development. The β-lapachone (bL) compound is widely used to treat cancer development; however, its effect on cancer stem cells remain elusive. Thus, we investigated the effect of bL on mammosphere formation using breast-cancer stem-cell (BCSC) marker-positive cells, MDA-MB-231. MDA-MB-231 cells, which are negative for reduced nicotinamide adenine dinucleotide phosphate (NAD(P)H):quinone oxidoreductase (NQO1) expression, were constructed to stably express NQO1 (NQO1 stable cells). The effect of bL on these cells was evaluated by wound healing and Transwell cell-culture chambers, ALDEFLUOR assay, and mammosphere formation assay. Here, we show that bL inhibited the proliferative ability of mammospheres derived from BCSC marker-positive cells, MDA-MB-231, in an NQO1-dependent manner. The bL treatment efficiently downregulated the expression level of BCSC markers cluster of differentiation 44 (CD44), aldehyde dehydrogenase 1 family member A1 (ALDH1A1), and discs large (DLG)-associated protein 5 (DLGAP5) that was recently identified as a stem-cell proliferation marker in both cultured cells and mammosphered cells. Moreover, bL efficiently downregulated cell proliferation and migration activities. These results strongly suggest that bL could be a therapeutic agent for targeting breast-cancer stem-cells with proper NQO1 expression.

High levels of proliferation regulators and an impaired senescence response pathway to identify early-stage breast tumors with a poor prognosis.

2013 ◽  
Vol 31 (26_suppl) ◽  
pp. 43-43
Author(s):  
Fiona T. Lanigan ◽  
Eiseart J. Dunne ◽  
Gerard L. Brien ◽  
Fatima Al Oraifi ◽  
Yue Fan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Early Stage ◽  
Primary Cultures ◽  
Cancer Recurrence ◽  
Recurrence Risk ◽  
Early Stage Breast Cancer ◽  
Breast Cancer Patients ◽  
Cancer Proliferation ◽  
Protein Levels ◽  
Clinical Biomarkers

43 Background: Predicting the risk of tumour recurrence, and thus the need for chemotherapy, for lymph node-negative breast cancer patients is a significant problem for clinicians and patients. Methods: We have identified a ‘core proliferation signature,’ which is consistently high in proliferating primary cultures, and is downregulated during cellular senescence. Using a reverse engineering approach on a breast cancer-specific regulatory network, and confirmed by ChIP-seq analysis, we have identified a hierarchy of several highly interconnected Master Transcriptional Regulators upstream of these core proliferation genes. Results: Further analysis of the expression of these factors in breast cancer cohorts at the mRNA and protein levels reveals a remarkable ability to reliably predict recurrence risk for early-stage breast cancer. Strikingly, in our analyses, a combination of just two of these factors outperforms the currently used clinical biomarkers for breast cancer recurrence risk, as well as recently developed multi-gene prognostic assays. Moreover, the addition of the senescence regulator p16INK4A to this panel further increases its prognostic capability. Conclusions: We propose that this novel approach has succeeded in identifying ‘drivers’ of breast cancer proliferation which, when combined with a marker of senescence such as p16INK4A, successfully identify actively proliferating tumours with an impaired senescence response pathway. Furthermore, we suggest that this gene combination has the potential to become an improved prognostic assay for early-stage breast cancer.

Tramtrack controls glial number and identity in the Drosophila embryonic CNS

Development ◽  
2001 ◽  
Vol 128 (20) ◽  
pp. 4093-4101 ◽  
Author(s):  
Paul Badenhorst
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Neural Stem Cell ◽  
System Analysis ◽  
Cell Formation ◽  
S Phase ◽  
Dependent Manner ◽  
Multipotent Stem Cells ◽  
Protein Levels ◽  
Cycle Dependent

Neurons and glia are often derived from common multipotent stem cells. In Drosophila, neural identity appears to be the default fate of these precursors. Stem cells that generate either neurons or glia transiently express neural stem cell-specific markers. Further development as glia requires the activation of glial-specific regulators. However, this must be accompanied by simultaneous repression of the alternate neural fate. I show that the Drosophila transcriptional repressor Tramtrack is a key repressor of neuronal fates. It is expressed at high levels in all mature glia of the embryonic central nervous system. Analysis of the temporal profile of Tramtrack expression in glia shows that it follows that of existing glial markers. When expressed ectopically before neural stem cell formation, Tramtrack represses the neural stem cell-specific genes asense and deadpan. Surprisingly, Tramtrack protein levels oscillate in a cell cycle-dependent manner in proliferating glia, with expression dropping before replication, but re-initiating after S phase. Overexpression of Tramtrack blocks glial development by inhibiting S-phase and repressing expression of the S-phase cyclin, cyclin E. Conversely, in tramtrack mutant embryos, glia are disrupted and undergo additional rounds of replication. I propose that Tramtrack ensures stable mature glial identity by both repressing neuroblast-specific genes and controlling glial cell proliferation.

scholarly journals O-Acetyl-GD2 as a Therapeutic Target for Breast Cancer Stem Cells

2022 ◽  
Vol 12 ◽  
Author(s):  
Jing-Yan Cheng ◽  
Jung-Tung Hung ◽  
Juway Lin ◽  
Fei-Yun Lo ◽  
Jing-Rong Huang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Tumor Growth ◽  
Dependent Manner ◽  
Breast Cancer Stem Cells ◽  
Lipid Molecule ◽  
Mammosphere Formation

SynopsisA sugar-lipid molecule called OAcGD2 is a novel marker for breast cancer stem cells. Treatment with anti-OAcGD2 mAb8B6 may have superior anticancer efficacy by targeting cancer stem cells, thereby reducing metastasis and recurrence of cancer.BackgroundCancer stem cells (CSCs) that drive tumor progression and disease recurrence are rare subsets of tumor cells. CSCs are relatively resistant to conventional chemotherapy and radiotherapy. Eradication of CSCs is thus essential to achieve durable responses. GD2 was reported to be a CSC marker in human triple-negative breast cancer, and anti-GD2 immunotherapy showed reduced tumor growth in cell lines. Using a specific anti-OAcGD2 antibody, mAb8D6, we set out to determine whether OAcGD2+ cells exhibit stem cell properties and mAb8D6 can inhibit tumor growth by targeting OAcGD2+CSCs.MethodOAcGD2 expression in patient-derived xenografts (PDXs) of breast cancer was determined by flow cytometric analyses using mAb8D6. The stemness of OAcGD2+ cells isolated by sorting and the effects of mAb8B6 were assessed by CSC growth and mammosphere formation in vitro and tumor growth in vivo using PDX models.ResultWe found that the OAcGD2 expression levels in six PDXs of various molecular subtypes of breast cancer highly correlated with their previously defined CSC markers in these PDXs. The sorted OAcGD2+ cells displayed a greater capacity for mammosphere formation in vitro and tumor initiation in vivo than OAcGD2− cells. In addition, the majority of OAcGD2+ cells were aldehyde dehydrogenase (ALDH+) or CD44hiCD24lo, the known CSC markers in breast cancer. Treatment of PDXs-bearing mice with mAb8B6, but not doxorubicin, suppressed the tumor growth, along with reduced CSCs as assessed by CSC markers and in vivo tumorigenicity. In vitro, mAb8B6 suppressed proliferation and mammosphere formation and induced apoptosis of OAcGD2+ breast cancer cells harvested from PDXs, in a dose-dependent manner. Finally, administration of mAb8B6 in vivo dramatically suppressed tumor growth of OAcGD2+ breast CSCs (BCSCs) with complete tumor abrogation in 3/6 mice.ConclusionOAcGD2 is a novel marker for CSC in various subtypes of breast cancer. Anti-OAcGD2 mAb8B6 directly eradicated OAcGD2+ cells and reduced tumor growth in PDX model. Our data demonstrate the potential of mAb8B6 as a promising immunotherapeutic agent to target BCSCs.

Inhibitory Effect of Hydroxysafflor Yellow B on the Proliferation of Human Breast Cancer MCF-7 Cells

2019 ◽  
Vol 14 (2) ◽  
pp. 187-197 ◽  
Author(s):  
Chuanjun Qu ◽  
Weiwei Zhu ◽  
Kaijie Dong ◽  
Zhaohai Pan ◽  
Ying Chen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Flow Cytometry ◽  
Cell Apoptosis ◽  
Human Breast Cancer ◽  
S Phase ◽  
Dependent Manner ◽  
Human Breast ◽  
Protein Levels ◽  
Mcf 7

Background:A recent patent has been issued for hydroxysafflor yellow A (HSYA) as a drug to prevent blood circulation disorders. Hydroxysafflor yellow B (HSYB), an isomer of HSYA with antioxidative effects, has been isolated from the florets of Carthamus tinctorius. The effects of HSYB on the proliferation of cancer cells and its mechanism of action have not been investigated.Objective:The aims of this study were to investigate the anti-cancer effects and the molecular mechanism of HSYB for breast cancer MCF-7 cells.Methods:MTT assays and colony formation assays were used to assess the survival and proliferation of MCF-7 cells, respectively. Hoechst 33258 and flow cytometry were used to measure cell apoptosis and flow cytometry to determine effects on the cell cycle. Western blots were used to measure protein levels.Results:Treatment with HSYB reduced survival and proliferation of human breast cancer MCF-7 cells in a dose-dependent manner. Furthermore, HSYB arrested the MCF-7 cell cycle at the S phase and downregulated cyclin D1, cyclin E, and CDK2. Compared with a control group, HSYB suppressed the protein levels of p-PI3K, PI3K, AKT, and p-AKT in MCF-7 cells. In addition, HSYB decreased the levels of Bcl- 2, increased the levels of Bax, cleaved caspase-3 and caspase-9, and subsequently induced MCF-7 cell apoptosis.Conclusion:These data demonstrate that HSYB arrests the MCF-7 cell cycle at the S phase and induces cell apoptosis. Patent US20170246228 indicates that HSYB can be potentially used for the prevention and treatment of human breast cancer.

scholarly journals Caudatin Isolated from Cynanchum auriculatum Inhibits Breast Cancer Stem Cell Formation via a GR/YAP Signaling

Biomolecules ◽  
2020 ◽  
Vol 10 (6) ◽  
pp. 925
Author(s):  
Xing Zhen ◽  
Hack Sun Choi ◽  
Ji-Hyang Kim ◽  
Su-Lim Kim ◽  
Ren Liu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gel Filtration ◽  
Cell Formation ◽  
Nuclear Accumulation ◽  
Cancer Cell Proliferation ◽  
Mammosphere Formation ◽  
Cynanchum Auriculatum ◽  
Inhibitory Compound ◽  
Mammosphere Assay ◽  
Transcription Signals

In the complex tumor microenvironment, cancer stem cells (CSCs), a rare population of cells, are responsible for malignant tumor initiation, metastasis, drug resistance and recurrence. Controlling breast CSCs (BCSCs) using natural compounds is a novel potential therapeutic strategy for clinical cancer treatment. In this study, a mammosphere assay-guided isolation protocol including silica gel, a C18 column, gel filtration, and high-pressure liquid chromatography was used to isolate an inhibitory compound from Cynanchum auriculatum extracts. The isolated inhibitory compound was identified as caudatin. Caudatin inhibited breast cancer cell proliferation, mammosphere formation and tumor growth. Caudatin decreased the CD44+/CD24− and aldehyde dehydrogenase+ cell proportions and the levels of c-Myc, Oct4, Sox2, and CD44. Caudatin induced ubiquitin (Ub)-dependent glucocorticoid receptor (GR) degradation and blocked subsequent Yes-associated protein (YAP) nuclear accumulation and target gene transcription signals in BCSCs. These results show that the GR/YAP signaling pathway regulates BCSC formation and that caudatin may be a potential chemopreventive agent that targets breast cancer cells and CSCs.

scholarly journals Machilin D, a Lignin Derived from Saururus chinensis, Suppresses Breast Cancer Stem Cells and Inhibits NF-κB Signaling

Biomolecules ◽  
2020 ◽  
Vol 10 (2) ◽  
pp. 245 ◽  
Author(s):  
Xing Zhen ◽  
Hack Sun Choi ◽  
Ji-Hyang Kim ◽  
Su-Lim Kim ◽  
Ren Liu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
High Performance ◽  
Reversed Phase ◽  
Breast Cancer Stem Cells ◽  
Mammosphere Formation ◽  
Saururus Chinensis ◽  
Isolated Compound ◽  
Layer Chromatography

Cancer stem cells are responsible for breast cancer initiation, metastasis, and relapse. Targeting breast cancer stem cells (BCSCs) using phytochemicals is a good strategy for the treatment of cancer. A silica gel, a reversed-phase C18 column (ODS), a Sephadex LH-20 gel, thin layer chromatography, and high-performance liquid chromatography (HPLC) were used for compound isolation from Saururus chinensis extracts. The isolated compound was identified as machilin D by mass spectrometry and nuclear magnetic resonance (NMR). Machilin D inhibited the growth and mammosphere formation of breast cancer cells and inhibited tumor growth in a xenograft mouse model. Machilin D reduced the proportions of CD44+/CD24- and aldehyde dehydrogenase 1 (ALDH1)-positive cells. Furthermore, this compound reduced the nuclear localization of the NF-κB protein and decreased the IL-6 and IL-8 secretion in mammospheres. These results suggest that machilin D blocks IL-6 and IL-8 signaling and induces CSC death and thus may be a potential agent targeting BCSCs.

scholarly journals Propofol Reduced Mammosphere Formation of Breast Cancer Stem Cells via PD-L1/Nanog In Vitro

2019 ◽  
Vol 2019 ◽  
pp. 1-9 ◽  
Author(s):  
Xiaobei Zhang ◽  
Fangxuan Li ◽  
Ying Zheng ◽  
Xiaokun Wang ◽  
Kaiyuan Wang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stem Cells ◽  
Cell Proliferation ◽  
Cancer Stem Cells ◽  
Cancer Recurrence ◽  
Tumor Formation ◽  
Breast Cancer Stem Cells ◽  
Mammosphere Formation ◽  
Significant Difference

Several researches revealed that propofol, a hypnotic intravenous anesthesia agent, could inhibit the cancer cell proliferation and tumor formation, which might affect cancer recurrence or metastasis and impact patients’ prognosis. Cancer stem cells (CSCs) comprised a tiny fraction of tumor bulk and played a vital role in cancer recurrence and eventual mortality. This study investigates the effect of propofol on breast cancer stem cells (BCSCs) in vitro and the underlying molecular mechanisms. Tumor formation of CSCs was measured by mammosphere culture. Cultured BCSCs were exposed to different concentrations and durations of propofol. Cell proliferation and self-renewal capacity were determined by MTT assays. Expressions of PD-L1 and Nanog were measured using western blotting and real-time PCR. We knocked down the PD-L1 expression in MDA-MB-231 cells by lentivirus-mediated RNAi technique, and the mammosphere-forming ability of shControl and shPD-L1 under propofol treatment was examined. Mammosphere culture could enrich BCSCs. Compared with control, cells exposed to propofol for 24 h induced a larger number of mammosphere cells (P=0.0072). Levels of PD-L1 and Nanog were downregulated by propofol. Compared with shControl stem cells, there was no significant difference in the inhibitory effect of propofol on the mammosphere-forming ability of shPD-L1 stem cells which indicated that the inhibition of propofol could disappear in PD-L1 knockdown breast stem cells. Propofol could reduce the mammosphere-forming ability of BCSCs in vitro. Mechanism experiments indicated that the inhibition of propofol in mammosphere formation of BCSCs might be mediated through PD-L1, which was important to maintain Nanog.

scholarly journals Prolactin/Stat5 and Androgen R1881 Coactivate Carboxypeptidase-D Gene in Breast Cancer Cells

2014 ◽  
Vol 28 (3) ◽  
pp. 331-343 ◽  
Author(s):  
Samir Koirala ◽  
Lynn N. Thomas ◽  
Catherine K. L. Too
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Promoter Activity ◽  
Luciferase Reporter ◽  
No Production ◽  
Dependent Manner ◽  
Protein Levels ◽  
Promoter Construct ◽  
Carboxypeptidase D

Abstract Plasma membrane-bound carboxypeptidase-D (CPD) cleaves C-terminal arginine from extracellular substrates. In the cell, arginine is converted to nitric oxide (NO). We have reported that up-regulation of CPD mRNA/protein levels by 17β-estradiol and prolactin (PRL) in breast cancer cells, and by testosterone in prostate cancer cells, increased NO production and cell survival. The CPD promoter contains a consensus γ-interferon-activated sequence (GAS) and 3 putative androgen response elements (ARE.1, ARE.2, ARE.3) that could potentially bind PRL-activated transcription factor Stat5 (signal transducer and activator of transcription 5) and the liganded androgen receptor (AR), respectively. This study showed that synthetic androgen R1881 and PRL elevated CPD mRNA/protein levels in human MCF-7 and T47D breast cancer cells in a time-/dose-dependent manner. PRL/R1881-elevated CPD expression was blocked by actinomycin-D, and a CPD promoter construct containing these GAS and AREs was stimulated by PRL or R1881, indicating transcriptional regulation by both hormones. Luciferase reporter assays showed that GAS and the adjacent ARE.1 only were active. Mutation of GAS in the ΔGAS-CPD construct (ARE.1 intact) abolished CPD promoter activity in response to PRL and, surprisingly, to R1881 as well. ΔGAS-CPD promoter activity was restored by PRL+R1881 in combination, and enhanced by ectopic Stat5, but abolished by Stat5 gene knockdown. Chromatin immunoprecipitation analysis confirmed binding of activated Stat5 and liganded AR to GAS and ARE.1, respectively. Activated Stat5 also induced binding of unliganded AR to ARE.1, and liganded AR induced binding of unactivated Stat5 to GAS. In summary, PRL and R1881, acting through Stat5 and AR, act cooperatively to stimulate CPD gene transcription in breast cancer cells.

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