scholarly journals Oxidized ATM promotes breast cancer stem cell enrichment through energy metabolism reprogram-mediated acetyl-CoA accumulation

2020 ◽  
Vol 11 (7) ◽  
Author(s):  
Dan Yang ◽  
Meixi Peng ◽  
Yixuan Hou ◽  
Yilu Qin ◽  
Xueying Wan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stem Cell ◽  
Energy Metabolism ◽  
Cancer Stem Cell ◽  
Tumor Hypoxia ◽  
Tca Cycle ◽  
Glycolytic Flux ◽  
Atp Citrate Lyase ◽  
Acetyl Coa ◽  
Mammosphere Formation

Abstract Cancer stem cell (CSC) is a challenge in the therapy of triple-negative breast cancer (TNBC). Intratumoral hypoxia is a common feature of solid tumor. Hypoxia may contribute to the maintenance of CSC, resulting in a poor efficacy of traditional treatment and recurrence of TNBC cases. However, the underlying molecular mechanism involved in hypoxia-induced CSC stemness maintenance remains unclear. Here, we report that hypoxia stimulated DNA double-strand breaks independent of ATM kinase activation (called oxidized ATM in this paper) play a crucial role in TNBC mammosphere formation and stemness maintenance by governing a specific energy metabolism reprogramming (EMR). Oxidized ATM up-regulates GLUT1, PKM2, and PDHa expressions to enhance the uptake of glucose and production of pyruvate rather than lactate products, which facilitates glycolytic flux to mitochondrial pyruvate and citrate, thus resulting in accumulation of cytoplasmic acetyl-CoA instead of the tricarboxylic acid (TCA) cycle by regulating ATP-citrate lyase (ACLY) activity. Our findings unravel a novel model of TNBC-CSC glucose metabolism and its functional role in maintenance of hypoxic TNBC-CSC stemness. This work may help us to develop new therapeutic strategies for TNBC 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.

scholarly journals The C-X-C Motif Chemokine Ligand 1 Sustains Breast Cancer Stem Cell Self-Renewal and Promotes Tumor Progression and Immune Escape Programs

2021 ◽  
Vol 9 ◽  
Author(s):  
Stefania Livia Ciummo ◽  
Luigi D’Antonio ◽  
Carlo Sorrentino ◽  
Cristiano Fieni ◽  
Paola Lanuti ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stem Cell ◽  
Cancer Stem Cell ◽  
Tumor Progression ◽  
Immune Escape ◽  
Epithelial Mesenchymal Transition ◽  
Breast Cancer Stem Cell ◽  
Self Renewal ◽  
Mesenchymal Transition ◽  
Mammosphere Formation

Breast cancer (BC) mortality is mainly due to metastatic disease, which is primarily driven by cancer stem cells (CSC). The chemokine C-X-C motif ligand-1 (CXCL1) is involved in BC metastasis, but the question of whether it regulates breast cancer stem cell (BCSC) behavior is yet to be explored. Here, we demonstrate that BCSCs express CXCR2 and produce CXCL1, which stimulates their proliferation and self-renewal, and that CXCL1 blockade inhibits both BCSC proliferation and mammosphere formation efficiency. CXCL1 amplifies its own production and remarkably induces both tumor-promoting and immunosuppressive factors, including SPP1/OPN, ACKR3/CXCR7, TLR4, TNFSF10/TRAIL and CCL18 and, to a lesser extent, immunostimulatory cytokines, including IL15, while it downregulates CCL2, CCL28, and CXCR4. CXCL1 downregulates TWIST2 and SNAI2, while it boosts TWIST1 expression in association with the loss of E-Cadherin, ultimately promoting BCSC epithelial-mesenchymal transition. Bioinformatic analyses of transcriptional data obtained from BC samples of 1,084 patients, reveals that CXCL1 expressing BCs mostly belong to the Triple-Negative (TN) subtype, and that BC expression of CXCL1 strongly correlates with that of pro-angiogenic and cancer promoting genes, such as CXCL2-3-5-6, FGFBP1, BCL11A, PI3, B3GNT5, BBOX1, and PTX3, suggesting that the CXCL1 signaling cascade is part of a broader tumor-promoting signaling network. Our findings reveal that CXCL1 functions as an autocrine growth factor for BCSCs and elicits primarily tumor progression and immune escape programs. Targeting the CXCL1/CXCR2 axis could restrain the BCSC compartment and improve the treatment of aggressive BC.

Regulational effects of breast cancer stromal cells and normal breast stromal cells on MCF-7 mammosphere formation

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 1056-1056
Author(s):  
F. Zhang ◽  
Y. Xu ◽  
C. Song ◽  
Y. Ma ◽  
F. Nan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stem Cell ◽  
Cancer Stem Cell ◽  
Stromal Cells ◽  
Real Time Pcr ◽  
Normal Breast ◽  
Control Group ◽  
Mammosphere Formation ◽  
Forming Efficiency ◽  
Mcf 7

1056 Background: It is well known that microenvironment plays an important role in tumor progression so we investigated the regulatory effects of breast cancer stromal cells (BCSCs) and normal breast stromal cells (NBSCs) as microenvironment on MCF-7 mammosphere formation. Methods: MCF-7 cells were cultured in suspension to generate mammospheres. The proportion of CD44+CD24- cells was assessed by flow cytometry and the expression of Wint1, notch1, β-catenin, CXCR4, SOX2, and ALDH3A1 was detected by real-time PCR. The stromal cells were purified and identified by immumohistochemistry. BCSCs or NBSCs and MCF-7 cells were co-cultured via Transwell system, the volumes and numbers of mammospheres and the mammosphere-forming efficiency (MFE) were calculated and the expression of Wnt1, β-catenin, Notch1 were detected. Results: The proportion of CD44+CD24- cells in mammospheres and MCF-7 cells was 10.4% and 2.1% (p < 0.05), respectively. Real-time PCR analysis suggested that Wint1, notch1, β-catenin, CXCR4, SOX2, and ALDH3A1 genes in the mammosphere cells were with higher levels than MCF-7 cells by about 2.25, 2.45, 1.72, 4.68, 4.25, 5.38 fold, respectively (p < 0.01). The stromal cells purified were identified as fibroblasts by α-SMA,Vimentin and fibroblast special protein antibody via immumohistochemistry. The time of mammosphere's formation was earlier, the volumes of mammospheres were bigger, and the MFE was higher than control group. The expressions of Wnt1 in co-culture group were significantly upregulated 1.27, 3.18 folds than control group, respectively, while the β-catenin was 1.22, 1.75 folds; Notch1 was 1.31, 2.09 folds; and CXCR4 was 1.73, 2.77 folds, respectively. Conclusions: Mammosphere cells contained higher propotion of breast cancer stem cells and expressed higher levels of cancer stem cell related genes. BCSCs can promote the mammosphere-forming efficiency and upregulate the expression of cancer stem cell related genes. No significant financial relationships to disclose.

scholarly journals NF-kappaΒ-inducing kinase regulates stem cell phenotype in breast cancer

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Karla Vazquez-Santillan ◽  
Jorge Melendez-Zajgla ◽  
Luis Enrique Jimenez-Hernandez ◽  
Javier Gaytan-Cervantes ◽  
Laura Muñoz-Galindo ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stem Cell ◽  
Cancer Stem Cell ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Breast Cancer Cell Lines ◽  
Cell Phenotype ◽  
Activity Levels ◽  
Mammosphere Formation

Abstract Breast cancer stem cells (BCSCs) overexpress components of the Nuclear factor-kappa B (NF-κB) signaling cascade and consequently display high NF-κB activity levels. Breast cancer cell lines with high proportion of CSCs exhibit high NF-κB-inducing kinase (NIK) expression. The role of NIK in the phenotype of cancer stem cell regulation is poorly understood. Expression of NIK was analyzed by quantitative RT-PCR in BCSCs. NIK levels were manipulated through transfection of specific shRNAs or an expression vector. The effect of NIK in the cancer stem cell properties was assessed by mammosphere formation, mice xenografts and stem markers expression. BCSCs expressed higher levels of NIK and its inhibition through small hairpin (shRNA), reduced the expression of CSC markers and impaired clonogenicity and tumorigenesis. Genome-wide expression analyses suggested that NIK acts on ERK1/2 pathway to exert its activity. In addition, forced expression of NIK increased the BCSC population and enhanced breast cancer cell tumorigenicity. The in vivo relevance of these results is further supported by a tissue microarray of breast cancer samples in which we observed correlated expression of Aldehyde dehydrogenase (ALDH) and NIK protein. Our results support the essential involvement of NIK in BCSC phenotypic regulation via ERK1/2 and NF-κB.

scholarly journals miR-142-3p attenuates breast cancer stem cell characteristics and decreases radioresistance in vitro

Tumor Biology ◽  
2018 ◽  
Vol 40 (8) ◽  
pp. 101042831879188 ◽  
Author(s):  
Fabian M Troschel ◽  
Nicolas Böhly ◽  
Katrin Borrmann ◽  
Timo Braun ◽  
Alexander Schwickert ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stem Cells ◽  
Stem Cell ◽  
Cancer Stem Cells ◽  
Cancer Stem Cell ◽  
Quantitative Polymerase Chain Reaction ◽  
Breast Cancer Stem Cell ◽  
Stem Cell Markers ◽  
Western Blots ◽  
Mammosphere Formation

Effectively targeting cancer stem cells, a subpopulation of tumorigenic, aggressive, and radioresistant cells, holds therapeutic promise. However, the effects of the microRNA miR-142-3p, a small endogenous regulator of gene expression on breast cancer stem cells, have not been investigated. This study identifies the influence of miR-142-3p on mammary stemness properties and breast cancer radioresistance to establish its role in this setting. miR-142-3p precursor transfection was performed in MDA-MB-468, HCC1806, and MCF-7 cells, and stem cell markers CD44, CD133, ALDH1 activity and mammosphere formation were measured. β-catenin, the canonical wnt signaling effector protein, was quantified by Western blots and cell fluorescence assays both in miR-142-3p–overexpressing and anti–miR-142-3p–treated cells. Radiation response was investigated by colony formation assays. Levels of BRCA1, BRCA2, and Bod1 in miR-142-3p–overexpressing cells as well as expression of miR-142-3p, Bod1, KLF4, and Oct4 in sorted CD44+/CD24–/low cells were determined by quantitative polymerase chain reaction. miR-142-3p overexpression resulted in a strong decline in breast cancer stem cell characteristics with a decrease in CD44, CD133, ALDH1, Bod1, BRCA2, and mammosphere formation as well as reduced survival after irradiation. miR-142-3p expression was strongly reduced in sorted CD44+/CD24–/low stem cells, while Bod1, Oct4, and KLF4 were overexpressed. β-catenin levels strongly decreased after miR-142-3p overexpression, but not after anti–miR-142-3p treatment. We conclude that miR-142-3p downregulates cancer stem cell characteristics and radioresistance in breast cancer, mediated by a reduced role of β-catenin in miR-142-3p–overexpressing cells. miR-142-3p might therefore help to target cancer stem cells.

scholarly journals Coriolic Acid (13-(S)-Hydroxy-9Z, 11E-octadecadienoic Acid) from Glasswort (Salicornia herbacea L.) Suppresses Breast Cancer Stem Cell through the Regulation of c-Myc

Molecules ◽  
2020 ◽  
Vol 25 (21) ◽  
pp. 4950
Author(s):  
Yu-Chan Ko ◽  
Hack Sun Choi ◽  
Ji-Hyang Kim ◽  
Su-Lim Kim ◽  
Bong-Sik Yun ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stem Cells ◽  
Stem Cell ◽  
Cancer Stem Cells ◽  
Cancer Stem Cell ◽  
Ionization Mass ◽  
Mammosphere Formation ◽  
Bioassay Guided Fractionation ◽  
Myc Gene ◽  
Salicornia Herbacea

Cancer stem cells have certain characteristics, such as self-renewal, differentiation, and drug resistance, which are related to tumor progression, maintenance, recurrence, and metastasis. In our study, we targeted breast cancer stem cells (BCSCs) using a natural compound, coriolic acid, from Salicornia herbacea L. This compound was isolated by mammosphere formation inhibition bioassay-guided fractionation and identified by using NMR spectroscopy and electrospray ionization mass spectrometry. Coriolic acid inhibited the formation of mammospheres and induced BCSC apoptosis. It also decreased the subpopulation of CD44high/CD24low cells, a cancer stem cell (CSC) phenotype, and specific genes related to CSCs, such as Nanog,Oct4, and CD44. Coriolic acid decreased the transcriptional and translational levels of the c-Myc gene, which is a CSC survival factor. These results indicated that coriolic acid could be a novel compound to target BCSCs via regulation of c-Myc.

scholarly journals A Positive Feedback Loop Between c-Myc Upregulation, Glycolytic Shift, and Histone Acetylation Enhances Cancer Stem Cell-like Property and Tumorigenicity of Cr(VI)-transformed Cells

2020 ◽  
Vol 177 (1) ◽  
pp. 71-83
Author(s):  
Marco Clementino ◽  
Jie Xie ◽  
Ping Yang ◽  
Yunfei Li ◽  
Hsuan-Pei Lin ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cancer Stem Cell ◽  
Histone Acetylation ◽  
Positive Feedback ◽  
Feedback Loop ◽  
Cell Transformation ◽  
Transformed Cells ◽  
Atp Citrate Lyase ◽  
Acetyl Coa ◽  
Positive Feedback Loop

Abstract Chronic hexavalent chromium [Cr(VI)] exposure causes lung cancer and other types of cancer; however, the mechanism of Cr(VI) carcinogenesis remains to be clearly defined. Our recent study showed that chronic Cr(VI) exposure upregulates the proto oncogene c-Myc expression, which contributes significantly to Cr(VI)-induced cell transformation, cancer stem cell (CSC)-like property and tumorigenesis. c-Myc is a master regulator of cancer cell abnormal metabolism and accumulating evidence suggests that metabolism dysregulation plays an important role in both cancer development and progression. However, little is known about the role of metabolism dysregulation in Cr(VI) carcinogenesis. This study was performed to investigate the potential role and mechanism of metabolism dysregulation in Cr(VI) carcinogenesis. It was found that Cr(VI)-transformed cells display glycolytic shift, which depends on the upregulation of c-Myc. The glycolytic shift in Cr(VI)-transformed cells led to increased production of acetyl coenzyme A (acetyl-CoA) and elevation of histone acetylation. This, in turn, upregulated the expression of an acetyl-CoA producing key enzyme ATP citrate lyase and c-Myc, forming a positive feedback loop between the upregulation of c-Myc expression, glycolytic shift and increased histone acetylation. It was further determined that glucose depletion not only reverses the glycolytic shift in Cr(VI)-transformed cells, but also significantly reduces their growth, CSC-like property and tumorigenicity. These findings indicate that glycolytic shift plays an important role in maintaining malignant phenotypes of Cr(VI)-transformed cells, suggesting that metabolism dysregulation is critically involved in Cr(VI) carcinogenesis.

Regulation of Breast Cancer Stem Cell by Tissue Rigidity

2015 ◽  
Author(s):  
Jing Yang ◽  
Adam Engler ◽  
Laurent Fattet ◽  
Matthew Ondeck
Keyword(s):  
Breast Cancer ◽  
Stem Cell ◽  
Cancer Stem Cell ◽  
Breast Cancer Stem Cell

scholarly journals Isolation and Establishment of a Highly Proliferative, Cancer Stem Cell-Like, and Naturally Immortalized Triple-Negative Breast Cancer Cell Line, KAIMRC2

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1303
Author(s):  
Rizwan Ali ◽  
Hajar Al Zahrani ◽  
Tlili Barhoumi ◽  
Alshaimaa Alhallaj ◽  
Abdullah Mashhour ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stem Cell ◽  
Cancer Stem Cell ◽  
Cell Line ◽  
Cancer Cell ◽  
Triple Negative Breast Cancer ◽  
Breast Cancer Cell Line ◽  
Triple Negative ◽  
Cancer Cell Line

In vitro studies of a disease are key to any in vivo investigation in understanding the disease and developing new therapy regimens. Immortalized cancer cell lines are the best and easiest model for studying cancer in vitro. Here, we report the establishment of a naturally immortalized highly tumorigenic and triple-negative breast cancer cell line, KAIMRC2. This cell line is derived from a Saudi Arabian female breast cancer patient with invasive ductal carcinoma. Immunocytochemistry showed a significant ratio of the KAIMRC2 cells’ expressing key breast epithelial and cancer stem cells (CSCs) markers, including CD47, CD133, CD49f, CD44, and ALDH-1A1. Gene and protein expression analysis showed overexpression of ABC transporter and AKT-PI3Kinase as well as JAK/STAT signaling pathways. In contrast, the absence of the tumor suppressor genes p53 and p73 may explain their high proliferative index. The mice model also confirmed the tumorigenic potential of the KAIMRC2 cell line, and drug tolerance studies revealed few very potent candidates. Our results confirmed an aggressive phenotype with metastatic potential and cancer stem cell-like characteristics of the KAIMR2 cell line. Furthermore, we have also presented potent small molecule inhibitors, especially Ryuvidine, that can be further developed, alone or in synergy with other potent inhibitors, to target multiple cancer-related pathways.

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