scholarly journals SIRT7–SREBP1 restrains cancer cell metabolic reprogramming by upregulating IDH1

2021 ◽  
Author(s):  
Fengting Su ◽  
Xiaolong Tang ◽  
Guo Li ◽  
Andreas Koeberle ◽  
Baohua Liu
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Therapeutic Intervention ◽  
Warburg Effect ◽  
Lung Metastases ◽  
Cell Types ◽  
Metabolic Reprogramming ◽  
Protein Levels ◽  
Underlying Mechanisms

AbstractSIRT7 plays critical roles in tumorigenesis and tumor progression; however, the underlying mechanisms are poorly understood. Here, we aimed to identify downstream targets of SIRT7 to help delineate its precise function. In this study, we demonstrate that SIRT7 is essential to regulate IDH1 expression in various cancer cell types. Interestingly, both SIRT7 and IDH1 levels are downregulated in breast cancer lung metastases and are useful for predicting disease progression and prognosis. Mechanistically, SIRT7 enhances IDH1 transcription, and this process is mediated by SREBP1. SIRT7 insufficiency reduces cellular α-ketoglutarate, a metabolite product of IDH1, and suppresses lipogenesis and gluconeogenesis. Moreover, α-ketoglutarate decline increases HIF1α protein levels and, thus, promotes glycolysis. This effect permits cancer cells to facilitate Warburg effect and undergo fast proliferation. Overall, the SIRT7–IDH1 axis regulates cancer cell metabolic reprogramming and, thus, might serve as a point of therapeutic intervention.

scholarly journals Breast Cancer Cell Re-Dissemination from Lung Metastases—A Mechanism for Enhancing Metastatic Burden

2021 ◽  
Vol 10 (11) ◽  
pp. 2340
Author(s):  
Lucia Borriello ◽  
John Condeelis ◽  
David Entenberg ◽  
Maja H. Oktay
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Metastatic Disease ◽  
Breast Cancer Cells ◽  
Lung Metastases ◽  
Primary Tumors ◽  
Metastatic Burden ◽  
First Time ◽  
Do So

Although metastatic disease is the primary cause of mortality in cancer patients, the mechanisms leading to overwhelming metastatic burden are still incompletely understood. Metastases are the endpoint of a series of multi-step events involving cancer cell intravasation, dissemination to distant organs, and outgrowth to metastatic colonies. Here we show, for the first-time, that breast cancer cells do not solely disseminate to distant organs from primary tumors and metastatic nodules in the lymph nodes, but also do so from lung metastases. Thus, our findings indicate that metastatic dissemination could continue even after the removal of the primary tumor. Provided that the re-disseminated cancer cells initiate growth upon arrival to distant sites, cancer cell re-dissemination from metastatic foci could be one of the crucial mechanisms leading to overt metastases and patient demise. Therefore, the development of new therapeutic strategies to block cancer cell re-dissemination would be crucial to improving survival of patients with metastatic disease.

Potential Mechanisms of miR-143/Krupple Like Factor 5 Axis in Impeding the Proliferation of Michigan Cancer Foundation-7 Breast Cancer Cell Line

2021 ◽  
Vol 11 (2) ◽  
pp. 326-332
Author(s):  
Le Ma ◽  
Zhenyu Liu ◽  
Zhimin Fan
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Breast Cancer Cells ◽  
Cell Model ◽  
Cancer Cell Line ◽  
Breast Cancer Cell Model ◽  
Underlying Mechanisms ◽  
Mcf 7

Breast cancer is one of the most prevailing cancers in females, while the cancerous heterogeneity hinders its early diagnosis and subsequent therapy. miR-143-3p is a critical mediator in malignancy development and tumorigenesis as a tumor suppressor. Its role in various tumor entities has been investigated, such as colon cancer and breast cancer. Using MCF-7 breast cancer cell model, we planned to explore the underlying mechanisms of miR-143/KLF-5 axis in retarding breast cancer cells growth. Bioinformatics analysis searched the target KLF5 of miR-143, and the miR-143-targeted mimic and inhibitor were employed to detect the changes of KLF5. After transfection of mimic miR-143, the CCK-8 reagent assessed cell proliferation. Based on optimal stimulation time, miR-143 stimulation model was established, followed by determining expression of KLF5, EGFR and PCNA via western blot and qPCR. Eventually, siRNA-KLF5 was applied to silencing KLF5 level to evaluate its role in MCF-7 cells. The transcription and translation levels of KLF5 were diminished in miR-143-mimic transfected MCF-7 cells, while enhanced in miR-143-inhibitor transfected MCF-7 cells. When MCF-7 cells were transfected with miR-143-mimic at different time points, 48 hours was found to be the optimal transfection time, with reduced transcription and translation levels of KLF5, EGFR and PCNA. The transcription and translation levels of PNCA and EGFR were declined after silencing KLF5 by siRNA. miR-143/KLF5 axis could retard the proliferation of MCF-7 breast cancer cells.

scholarly journals Selective Effects of Thioridazine on Self-Renewal of Basal-Like Breast Cancer Cells

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Matthew Tegowski ◽  
Cheng Fan ◽  
Albert S. Baldwin
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Breast Cancer Cells ◽  
Cell Types ◽  
Breast Cancer Cell Lines ◽  
Breast Cancers ◽  
Self Renewal ◽  
Basal Like Breast Cancer

AbstractSeveral recent publications demonstrated that DRD2-targeting antipsychotics such as thioridazine induce proliferation arrest and apoptosis in diverse cancer cell types including those derived from brain, lung, colon, and breast. While most studies show that 10–20 µM thioridazine leads to reduced proliferation or increased apoptosis, here we show that lower doses of thioridazine (1–2 µM) target the self-renewal of basal-like breast cancer cells, but not breast cancer cells of other subtypes. We also show that all breast cancer cell lines tested express DRD2 mRNA and protein, regardless of thioridazine sensitivity. Further, DRD2 stimulation with quinpirole, a DRD2 agonist, promotes self-renewal, even in cell lines in which thioridazine does not inhibit self-renewal. This suggests that DRD2 is capable of promoting self-renewal in these cell lines, but that it is not active. Further, we show that dopamine can be detected in human and mouse breast tumor samples. This observation suggests that dopamine receptors may be activated in breast cancers, and is the first time to our knowledge that dopamine has been directly detected in human breast tumors, which could inform future investigation into DRD2 as a therapeutic target for breast cancer.

scholarly journals POU1F1 transcription factor induces metabolic reprogramming and breast cancer progression via LDHA regulation

Oncogene ◽  
2021 ◽  
Author(s):  
Anxo Martínez-Ordoñez ◽  
Samuel Seoane ◽  
Leandro Avila ◽  
Noemi Eiro ◽  
Manuel Macía ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Transcription Factor ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Cancer Progression ◽  
Breast Cancer Cells ◽  
Metabolic Reprogramming ◽  
Migration And Invasion ◽  
Breast Cancer Cell Lines

AbstractMetabolic reprogramming is considered hallmarks of cancer. Aerobic glycolysis in tumors cells has been well-known for almost a century, but specific factors that regulate lactate generation and the effects of lactate in both cancer cells and stroma are not yet well understood. In the present study using breast cancer cell lines, human primary cultures of breast tumors, and immune deficient murine models, we demonstrate that the POU1F1 transcription factor is functionally and clinically related to both metabolic reprogramming in breast cancer cells and fibroblasts activation. Mechanistically, we demonstrate that POU1F1 transcriptionally regulates the lactate dehydrogenase A (LDHA) gene. LDHA catalyzes pyruvate into lactate instead of leading into the tricarboxylic acid cycle. Lactate increases breast cancer cell proliferation, migration, and invasion. In addition, it activates normal-associated fibroblasts (NAFs) into cancer-associated fibroblasts (CAFs). Conversely, LDHA knockdown in breast cancer cells that overexpress POU1F1 decreases tumor volume and [18F]FDG uptake in tumor xenografts of mice. Clinically, POU1F1 and LDHA expression correlate with relapse- and metastasis-free survival. Our data indicate that POU1F1 induces a metabolic reprogramming through LDHA regulation in human breast tumor cells, modifying the phenotype of both cancer cells and fibroblasts to promote cancer progression.

scholarly journals Poldip2 is an oxygen-sensitive protein that controls PDH and αKGDH lipoylation and activation to support metabolic adaptation in hypoxia and cancer

2018 ◽  
Vol 115 (8) ◽  
pp. 1789-1794 ◽  
Author(s):  
Felipe Paredes ◽  
Kely Sheldon ◽  
Bernard Lassègue ◽  
Holly C. Williams ◽  
Elizabeth A. Faidley ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Cancer Cell ◽  
Substrate Inhibition ◽  
Mitochondrial Protein ◽  
Hypoxia Inducible Factor ◽  
Cell Types ◽  
Metabolic Reprogramming ◽  
Metabolic Adaptation ◽  
Prosthetic Group ◽  
Catabolic Enzymes

Although the addition of the prosthetic group lipoate is essential to the activity of critical mitochondrial catabolic enzymes, its regulation is unknown. Here, we show that lipoylation of the pyruvate dehydrogenase and α-ketoglutarate dehydrogenase (αKDH) complexes is a dynamically regulated process that is inhibited under hypoxia and in cancer cells to restrain mitochondrial respiration. Mechanistically, we found that the polymerase-δ interacting protein 2 (Poldip2), a nuclear-encoded mitochondrial protein of unknown function, controls the lipoylation of the pyruvate and α-KDH dihydrolipoamide acetyltransferase subunits by a mechanism that involves regulation of the caseinolytic peptidase (Clp)-protease complex and degradation of the lipoate-activating enzyme Ac-CoA synthetase medium-chain family member 1 (ACSM1). ACSM1 is required for the utilization of lipoic acid derived from a salvage pathway, an unacknowledged lipoylation mechanism. In Poldip2-deficient cells, reduced lipoylation represses mitochondrial function and induces the stabilization of hypoxia-inducible factor 1α (HIF-1α) by loss of substrate inhibition of prolyl-4-hydroxylases (PHDs). HIF-1α–mediated retrograde signaling results in a metabolic reprogramming that resembles hypoxic and cancer cell adaptation. Indeed, we observe that Poldip2 expression is down-regulated by hypoxia in a variety of cell types and basally repressed in triple-negative cancer cells, leading to inhibition of lipoylation of the pyruvate and α-KDH complexes and mitochondrial dysfunction. Increasing mitochondrial lipoylation by forced expression of Poldip2 increases respiration and reduces the growth rate of cancer cells. Our work unveils a regulatory mechanism of catabolic enzymes required for metabolic plasticity and highlights the role of Poldip2 as key during hypoxia and cancer cell metabolic adaptation.

scholarly journals Curcumin as an Anti-Proliferative Agent in Breast Cancer through RASSF1A, Bax, and Caspase-3 Protein

2021 ◽  
Vol 2 (1) ◽  
pp. 19-27
Author(s):  
Nunung Ainur Rahma ◽  
Harliansyah ◽  
Fransiscus D. Suyatna ◽  
Mpu Kanoko ◽  
Primariadewi Rustamadji ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Caspase 3 ◽  
Cell Types ◽  
Specific Mechanism ◽  
Protein Levels ◽  
Bax Protein ◽  
The Relationship ◽  
Apoptotic Mechanism

Introduction: Curcumin is a polyphenol that has pharmacological activity that can inhibit tumor cell growth and induce apoptosis through various mechanisms. However, the specific mechanism of curcumin cytotoxicity remains controversial because of many anti- and pro-apoptotic signaling pathways in various cell types. This study aims to examine the relationship among curcumin on RASSF1A, Bax protein levels, and caspase-3 activity in supporting the apoptotic mechanism in CSA03 breast cancer cells. Method: Curcumin administration to cancer cells is based on differences in dosage with 24-hour incubation. Cytotoxicity after curcumin administration was determined using MTS. RASSF1A and Bax protein levels were tested through ELISA. Caspase-3 activity was used to determine apoptosis and was tested using flow cytometry. Results: The results indicated that curcumin had a cytotoxicity effect of 40.85 µg/mL. At concentrations of 40 µg/mL and 50 µg/mL, curcumin increases levels of protein RASSF1A (∆ = 26.53% and 47.35%, respectively), Bax (∆ = 48.79% and 386.15%), and caspase-3 (∆ = 1,678.51% and 1,871.889%) significantly. Conclusions: Curcumin exhibits anti-proliferative activity and apoptotic (Caspase-3) effects through activation of RASSF1A and Bax.

scholarly journals Thioridazine inhibits self-renewal in breast cancer cells via DRD2-dependent STAT3 inhibition, but induces a G1 arrest independent of DRD2

2018 ◽  
Vol 293 (41) ◽  
pp. 15977-15990 ◽  
Author(s):  
Matthew Tegowski ◽  
Cheng Fan ◽  
Albert S. Baldwin
Keyword(s):  
Breast Cancer ◽  
Cell Viability ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Cell Types ◽  
Breast Cancer Cell Lines ◽  
G1 Arrest ◽  
Cancer Cell Proliferation ◽  
Self Renewal

Thioridazine is an antipsychotic that has been shown to induce cell death and inhibit self-renewal in a broad spectrum of cancer cells. The mechanisms by which these effects are mediated are currently unknown but are presumed to result from the inhibition of dopamine receptor 2 (DRD2). Here we show that the self-renewal of several, but not all, triple-negative breast cancer cell lines is inhibited by thioridazine. The inhibition of self-renewal by thioridazine in these cells is mediated by DRD2 inhibition. Further, we demonstrate that DRD2 promotes self-renewal in these cells via a STAT3- and IL-6–dependent mechanism. We also show that thioridazine induces a G1 arrest and a loss in cell viability in all tested cell lines. However, the reduction in proliferation and cell viability is independent of DRD2 and STAT3. Our results indicate that although there are cell types in which DRD2 inhibition results in inhibition of STAT3 and self-renewal, the dramatic block in cancer cell proliferation across many cell lines caused by thioridazine treatment is independent of DRD2 inhibition.

scholarly journals Lipid Profile and Aquaporin Expression under Oxidative Stress in Breast Cancer Cells of Different Malignancies

2019 ◽  
Vol 2019 ◽  
pp. 1-10 ◽  
Author(s):  
Claudia Rodrigues ◽  
Lidija Milkovic ◽  
Ivana Tartaro Bujak ◽  
Marko Tomljanovic ◽  
Graça Soveral ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Lipid Profile ◽  
Cancer Cells ◽  
Triple Negative ◽  
Cell Types ◽  
Metabolic Reprogramming ◽  
Breast Cancer Cell Lines ◽  
Her2 Positive ◽  
Oxidative Challenge

Breast cancer is the major cause of tumor-associated mortality in women worldwide, with prognosis depending on the early discovery of the disease and on the type of breast cancer diagnosed. Among many factors, lipids could contribute to breast cancer malignancy by participating in cellular processes. Also, aquaporins are membrane channels found aberrantly expressed in cancer tissues that were correlated with tumor aggressiveness, progression, and metastasis. However, the differences in lipid profile and aquaporin expression between cell types of different malignant potential have never been investigated. Here, we selected three breast cancer cell lines representing the three major breast cancer types (hormone positive, HER2NEU positive, and triple negative) and analyzed their lipid profile and steady state lipid hydroperoxide levels to correlate with cell sensitivity to H2O2. Additionally, the expression profiles of AQP1, AQP3, and AQP5 and the Nrf2 transcription factor were evaluated, before and after oxidative challenge. We found that the lipid profile was dependent on the cell type, with the HER2-positive cells having the lowest level PUFA, whereas the triple negative showed the highest. However, in triple-negative cancer cells, a lower level of the Nrf2 may be responsible for a higher sensitivity to H2O2 challenge. Interestingly, HER2-positive cells showed the highest increase in intracellular ROS after oxidative challenge, concomitant with a significantly higher level of AQP1, AQP3, and AQP5 expression compared to the other cell types, with AQP3 always being the most expressed isoform. The AQP3 gene expression was stimulated by H2O2 treatment in hormone-positive and HER2NEU cells, together with Nrf2 expression, but was downregulated in triple-negative cells that showed instead upregulation of AQP1 and AQP5. The lipid profile and AQP gene expression after oxidative challenge of these particularly aggressive cell types may represent metabolic reprogramming of cancer cells and reflect a role in adaptation to stress and therapy resistance.

scholarly journals miR-107 enhances the sensitivity of breast cancer cells to paclitaxel

Open Medicine ◽  
2019 ◽  
Vol 14 (1) ◽  
pp. 456-466 ◽  
Author(s):  
Changpo Ma ◽  
Xuejun Shi ◽  
Wenchao Guo ◽  
Jianxin Niu ◽  
Guangshun Wang
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Chinese Women ◽  
Luciferase Reporter ◽  
Breast Cancer Patients ◽  
Protein Levels ◽  
Tumor Tissues ◽  
Cancer Tumor ◽  
Underlying Mechanisms

AbstractBreast cancer remains the most commonly diagnosed cancer in Chinese women. Paclitaxel (PTX) is a chemotherapy medication used to treat breast cancer patients. However, a side effect of paclitaxel is the severe drug resistance. Previous studies demonstrated that dysregulation of microRNAs could regulate sensitivity to paclitaxel in breast cancer. Here, the present study aimed to lucubrate the underlying mechanisms of miR-107 in regulating the sensitivity of breast cancer cells to PTX. The results demonstrated that miR-107 was down-regulated in breast cancer tumor tissues, while TPD52 was significantly up-regulated compared with the non-tumor adjacent tissues. After confirming that TPD52 may be a major target of miR-107 via a dual-luciferase reporter assay, the western blot and RT-qPCR assays further demonstrated that miR-107 may reduce the expression level of TPD52 as well. In addition, miR-107 may prominently enhance PTX induced reduction of cell viability and the promotion of cell apoptosis in breast cancer, and the variation could be reversed by co-transfected with pcDNA3.1-TPD52. Finally, miR-107 could further reduce the decreased expression of TPD52, Wnt1, β-catenin and cyclin D1 that was induced by PTX in both mRNA and protein levels, which were rescued by pcDNA3.1-TPD52 indicating that miR-107 regulated breast cancer cell sensitivity to PTX may be targeting TPD52 through Wnt/β-catenin signaling pathway.

scholarly journals Potential Role of MSC/Cancer Cell Fusion and EMT for Breast Cancer Stem Cell Formation

Cancers ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 1432 ◽  
Author(s):  
Ralf Hass ◽  
Juliane von der Ohe ◽  
Hendrik Ungefroren
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cell Fusion ◽  
Cancer Cell ◽  
Epithelial Mesenchymal Transition ◽  
Cell Formation ◽  
Metastatic Potential ◽  
Cell Types ◽  
Resistance Mechanisms ◽  
Mesenchymal Transition

Solid tumors comprise of maturated cancer cells and self-renewing cancer stem-like cells (CSCs), which are associated with various other nontumorigenic cell populations in the tumor microenvironment. In addition to immune cells, endothelial cells, fibroblasts, and further cell types, mesenchymal stroma/stem-like cells (MSC) represent an important cell population recruited to tumor sites and predominantly interacting with the different cancer cells. Breast cancer models were among the first to reveal distinct properties of CSCs, however, the cellular process(es) through which these cells are generated, maintained, and expanded within neoplastic tissues remains incompletely understood. Here, we discuss several possible scenarios that are not mutually exclusive but may even act synergistically: fusion of cancer cells with MSC to yield hybrid cells and/or the induction of epithelial-mesenchymal transition (EMT) in breast cancer cells by MSC, which can relay signals for retrodifferentiation and eventually, the generation of breast CSCs (BCSCs). In either case, the consequences may be promotion of self-renewal capacity, tumor cell plasticity and heterogeneity, an increase in the cancer cells’ invasive and metastatic potential, and the acquisition of resistance mechanisms towards chemo- or radiotherapy. While specific signaling mechanisms involved in each of these properties remain to be elucidated, the present review article focusses on a potential involvement of cancer cell fusion and EMT in the development of breast cancer stem cells.

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