scholarly journals Potent Anticancer Effect of the Natural Steroidal Saponin Gracillin Is Produced by Inhibiting Glycolysis and Oxidative Phosphorylation-Mediated Bioenergetics

Cancers ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 913 ◽  
Author(s):  
Hye-Young Min ◽  
Honglan Pei ◽  
Seung Yeob Hyun ◽  
Hye-Jin Boo ◽  
Hyun-Ji Jang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Oxidative Phosphorylation ◽  
Cancer Cells ◽  
Anticancer Agent ◽  
Aerobic Glycolysis ◽  
Cancer Cell Line ◽  
Steroidal Saponin ◽  
Antitumor Effects ◽  
Metabolic Switch ◽  
Atp Production

Metabolic rewiring to utilize aerobic glycolysis is a hallmark of cancer. However, recent findings suggest the role of mitochondria in energy generation in cancer cells and the metabolic switch to oxidative phosphorylation (OXPHOS) in response to the blockade of glycolysis. We previously demonstrated that the antitumor effect of gracillin occurs through the inhibition of mitochondrial complex II-mediated energy production. Here, we investigated the potential of gracillin as an anticancer agent targeting both glycolysis and OXPHOS in breast and lung cancer cells. Along with the reduction in adenosine triphosphate (ATP) production, gracillin markedly suppresses the production of several glycolysis-associated metabolites. A docking analysis and enzyme assay suggested phosphoglycerate kinase 1 (PGK1) is a potential target for the antiglycolytic effect of gracillin. Gracillin reduced the viability and colony formation ability of breast cancer cells by inducing apoptosis. Gracillin displayed efficacious antitumor effects in mice bearing breast cancer cell line or breast cancer patient-derived tumor xenografts with no overt changes in body weight. An analysis of publicly available datasets further suggested that PGK1 expression is associated with metastasis status and poor prognosis in patients with breast cancer. These results suggest that gracillin is a natural anticancer agent that inhibits both glycolysis and mitochondria-mediated bioenergetics.

scholarly journals Contribution by different fuels and metabolic pathways to the total ATP turnover of proliferating MCF-7 breast cancer cells

2002 ◽  
Vol 364 (1) ◽  
pp. 309-315 ◽  
Author(s):  
Michael GUPPY ◽  
Peter LEEDMAN ◽  
XinLin ZU ◽  
Victoria RUSSELL
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cancer Metabolism ◽  
Aerobic Glycolysis ◽  
Cancer Cell Line ◽  
Cell Types ◽  
Atp Production ◽  
Atp Turnover ◽  
Innovative System ◽  
Mcf 7

For the past 70 years the dominant perception of cancer metabolism has been that it is fuelled mainly by glucose (via aerobic glycolysis) and glutamine. Consequently, investigations into the diagnosis, treatment and the basic metabolism of cancer cells have been directed by this perception. However, the data on cancer metabolism are equivocal, and in this study we have sought to clarify the issue. Using an innovative system we have measured the total ATP turnover of the MCF-7 breast cancer cell line, the contributions to this turnover by oxidative and glycolytic ATP production and the contributions to the oxidative component by glucose, lactate, glutamine, palmitate and oleate. The total ATP turnover over approx. 5days was 26.8μmol of ATP·107 cells−1·h−1. ATP production was 80% oxidative and 20% glycolytic. Contributions to the oxidative component were approx. 10% glucose, 14% glutamine, 7% palmitate, 4% oleate and 65% from unidentified sources. The contribution by glucose (glycolysis and oxidation) to total ATP turnover was 28.8%, glutamine contributed 10.7% and glucose and glutamine combined contributed 40%. Glucose and glutamine are significant fuels, but they account for less than half of the total ATP turnover. The contribution of aerobic glycolysis is not different from that in a variety of other non-transformed cell types.

scholarly journals Transcriptomics and Metabolomics Integration Reveals Redox-Dependent Metabolic Rewiring in Breast Cancer Cells

Cancers ◽  
2021 ◽  
Vol 13 (20) ◽  
pp. 5058
Author(s):  
Marcella Bonanomi ◽  
Noemi Salmistraro ◽  
Giulia Fiscon ◽  
Federica Conte ◽  
Paola Paci ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Aerobic Glycolysis ◽  
Critical Role ◽  
Cancer Cell Line ◽  
Redox Balance ◽  
Ros Generation ◽  
Nucleotide Synthesis ◽  
Transcriptional Reprogramming ◽  
Rapid Generation

Rewiring glucose metabolism toward aerobic glycolysis provides cancer cells with a rapid generation of pyruvate, ATP, and NADH, while pyruvate oxidation to lactate guarantees refueling of oxidized NAD+ to sustain glycolysis. CtPB2, an NADH-dependent transcriptional co-regulator, has been proposed to work as an NADH sensor, linking metabolism to epigenetic transcriptional reprogramming. By integrating metabolomics and transcriptomics in a triple-negative human breast cancer cell line, we show that genetic and pharmacological down-regulation of CtBP2 strongly reduces cell proliferation by modulating the redox balance, nucleotide synthesis, ROS generation, and scavenging. Our data highlight the critical role of NADH in controlling the oncogene-dependent crosstalk between metabolism and the epigenetically mediated transcriptional program that sustains energetic and anabolic demands in cancer cells.

scholarly journals Regulation of Tumor Metabolism and Extracellular Acidosis by the TIMP-10–CD63 Axis in Breast Carcinoma

Cells ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 2721
Author(s):  
Abdo Najy ◽  
Young-Suk Jung ◽  
Seongho Kim ◽  
Rafael Fridman ◽  
Hyeong-Reh Kim
Keyword(s):  
Breast Cancer ◽  
Breast Carcinoma ◽  
Cell Survival ◽  
Cancer Cells ◽  
Aerobic Glycolysis ◽  
Tumor Metabolism ◽  
Cell Surface Receptor ◽  
Metabolic Switch ◽  
Extracellular Acidosis ◽  
Signaling Axis

A hallmark of malignant solid tumor is extracellular acidification coupled with metabolic switch to aerobic glycolysis. Using the human MCF10A progression model of breast cancer, we show that glycolytic switch and extracellular acidosis in aggressive cancer cells correlate with increased expression of tissue inhibitor of metalloproteinase-1 (TIMP-1), known to induce intracellular signal transduction through the interaction with its cell surface receptor CD63, independent of its metalloproteinase inhibitory function. We found that, in aggressive breast carcinoma, the TIMP-1–CD63 signaling axis induced a metabolic switch by upregulating the rate of aerobic glycolysis, lowering mitochondrial respiration, preventing intracellular acidification, and inducing extracellular acidosis. Carbonic anhydrase IX (CAIX), a regulator of cellular pH through the hydration of metabolically released pericellular CO2, was identified as a downstream mediator of the TIMP-1–CD63 signaling axis responsible for extracellular acidosis. Consistently with our previous study, the TIMP-1–CD63 signaling promoted survival of breast cancer cells. Interestingly, breast carcinoma cell survival was drastically reduced upon shRNA-mediated knockdown of CAIX expression, demonstrating the significance of CAIX-regulated pH in the TIMP-1–CD63-mediated cancer cell survival. Taken together, the present study demonstrates the functional significance of TIMP-1–CD63–CAXI signaling axis in the regulation of tumor metabolism, extracellular acidosis, and survival of breast carcinoma. We propose that this axis may serve as a novel therapeutic target.

scholarly journals Mucoxin (Acetogenin) Reduces Proinflammatory Cytokines in Breast Cancer

2019 ◽  
Vol 12 (1) ◽  
pp. 479-483
Author(s):  
Muhartono Muhartono ◽  
Subeki Subeki ◽  
Rizki Hanriko
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Proinflammatory Cytokines ◽  
Breast Cancer Cells ◽  
Anticancer Agent ◽  
Cancer Cell Line ◽  
Tnf Α ◽  
Induced Apoptosis ◽  
All Treatment ◽  
Mcf 7

Mucoxin is a potential compound used as an anticancer agent. Mucoxin induced apoptosis and inhibit proliferation in T47D breast cancer cells line. This study aims to determine the effect of mucoxin on proinflammatory cytokines in breast cancer. Proinflammatorycytokines play important role in the development and metastasis of cancer cells. Breast cancer cell line MCF-7 were grouped into five groups referred to mucoxin doses assays, they are 0 ng/mL; 0,1ng/mL; 0,5 ng/mL; 1 ng/mL; 5 ng/mL with three replication of each. Mucoxin was given for 48 hours. The levels of IL 6 and TNF-α assayed using ELISA methods. The results showed mucoxin decreases IL 6 levels in all treatment doses, but was not significant. Mucoxin also decreases TNF-α levels, with a significant reduction occurring at doses of 1 ng/mL and 5 ng/mL. It is suggested that mucoxin has potent to inhibit proinflammatory cytokines that play a role in the development and metastasis of breast cancer.

scholarly journals SIPA1 Enhances Aerobic Glycolysis Through HIF-2α Pathway to Promote Breast Cancer Metastasis

2022 ◽  
Vol 9 ◽  
Author(s):  
Chenguang Yao ◽  
Jun Weng ◽  
Lingyun Feng ◽  
Wanjun Zhang ◽  
Yan Xu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Oxidative Phosphorylation ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Cancer Metastasis ◽  
Aerobic Glycolysis ◽  
Metastatic Breast ◽  
Aberrant Expression ◽  
Ambient Oxygen

Increased dependence on aerobic glycolysis is characteristic of most cancer cells, whereas the mechanism underlying the promotion of aerobic glycolysis in metastatic breast cancer cells under ambient oxygen has not been well understood. Here, we demonstrated that aberrant expression of signal-induced proliferation-associated 1 (SIPA1) enhanced aerobic glycolysis and altered the main source of ATP production from oxidative phosphorylation to glycolysis in breast cancer cells. We revealed that SIPA1 promoted the transcription of EPAS1, which is known as the gene encoding hypoxia-inducible factor-2α (HIF-2α) and up-regulated the expression of multiple glycolysis-related genes to increase aerobic glycolysis. We also found that blocking aerobic glycolysis by either knocking down SIPA1 expression or oxamate treatment led to the suppression of tumor metastasis of breast cancer cells both in vitro and in vivo. Taken together, aberrant expression of SIPA1 resulted in the alteration of glucose metabolism from oxidative phosphorylation to aerobic glycolysis even at ambient oxygen levels, which might aggravate the malignancy of breast cancer cells. The present findings indicate a potential target for the development of therapeutics against breast cancers with dysregulated SIPA1 expression.

A Novel Triazole Derivative Drug Presenting In Vitro and In Vivo Anticancer Properties

2018 ◽  
Vol 18 (17) ◽  
pp. 1483-1493
Author(s):  
Ricardo Imbroisi Filho ◽  
Daniel T.G. Gonzaga ◽  
Thainá M. Demaria ◽  
João G.B. Leandro ◽  
Dora C.S. Costa ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cell Line ◽  
Cancer Cell ◽  
Cancer Cell Line ◽  
Hepatic Function ◽  
Anticancer Properties ◽  
Mcf 7

Background: Cancer is a major cause of death worldwide, despite many different drugs available to treat the disease. This high mortality rate is largely due to the complexity of the disease, which results from several genetic and epigenetic changes. Therefore, researchers are constantly searching for novel drugs that can target different and multiple aspects of cancer. Experimental: After a screening, we selected one novel molecule, out of ninety-four triazole derivatives, that strongly affects the viability and proliferation of the human breast cancer cell line MCF-7, with minimal effects on non-cancer cells. The drug, named DAN94, induced a dose-dependent decrease in MCF-7 cells viability, with an IC50 of 3.2 ± 0.2 µM. Additionally, DAN94 interfered with mitochondria metabolism promoting reactive oxygen species production, triggering apoptosis and arresting the cancer cells on G1/G0 phase of cell cycle, inhibiting cell proliferation. These effects are not observed when the drug was tested in the non-cancer cell line MCF10A. Using a mouse model with xenograft tumor implants, the drug preventing tumor growth presented no toxicity for the animal and without altering biochemical markers of hepatic function. Results and Conclusion: The novel drug DAN94 is selective for cancer cells, targeting the mitochondrial metabolism, which culminates in the cancer cell death. In the end, DAN94 has been shown to be a promising drug for controlling breast cancer with minimal undesirable effects.

Continuous Hypoxia and Glucose Metabolism, The Effects on Genes Expression in Mcf7 Breast Cancer Cell Line

2020 ◽  
Vol 20 ◽  
Author(s):  
Abdel Qader Al Bawab ◽  
Malek Zihlif ◽  
Yazan Jarrar ◽  
Ahmad Saleh
Keyword(s):  
Breast Cancer ◽  
Glucose Metabolism ◽  
Cancer Cells ◽  
Cell Line ◽  
Breast Cancer Cell Line ◽  
Warburg Effect ◽  
Cancer Cell Line ◽  
Mcf7 Cells ◽  
Genetic Changes ◽  
Genes Expression

Background: Hypoxia (deprived oxygen in tissues) may induce molecular and genetic changes in cancer cells. Objective: Investigating the genetic changes of glucose metabolism in breast cancer cell line (MCF7) after exposure to continuous hypoxia (10 and 20 cycles exposure of 72 hours continuously on a weekly basis). Method: Gene expression of MCF7 cells was evaluated using real-time polymerase chain reaction- array method. Furthermore, cell migration and wound healing assays were also applied. Results: It was found that 10 episodes of continuous hypoxia activated Warburg effect in MCF7 cells via the significant up-regulation of genes involved in glycolysis (ANOVA, p value < 0.05). The molecular changes were associated with the ability of MCF7 cells to divide and migrate. Interestingly, after 20 episodes of continuous hypoxia, the expression glycolysis mediated genes has dropped significantly (from 30 to 9 folds). This could be attributed to the adaptive ability of cancer cells. Conclusion: It is concluded that 10 hypoxic episodes increased the survival rate and the aggressiveness of MCF7 cells and induced Warburg effect by up-regulation of the glycolysis mediating genes expression.

scholarly journals Role of Sialyl-O-Acetyltransferase CASD1 on GD2 Ganglioside O-Acetylation in Breast Cancer Cells

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1468
Author(s):  
Sumeyye Cavdarli ◽  
Larissa Schröter ◽  
Malena Albers ◽  
Anna-Maria Baumann ◽  
Dorothée Vicogne ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Cancer Cell Line ◽  
Wild Type ◽  
Cellular Models ◽  
Promising Therapeutic Target ◽  
Plasmid Transfection ◽  
Ganglioside Species

The O-acetylated form of GD2, almost exclusively expressed in cancerous tissues, is considered to be a promising therapeutic target for neuroectoderm-derived tumors, especially for breast cancer. Our recent data have shown that 9-O-acetylated GD2 (9-OAcGD2) is the major O-acetylated ganglioside species in breast cancer cells. In 2015, Baumann et al. proposed that Cas 1 domain containing 1 (CASD1), which is the only known human sialyl-O-acetyltransferase, plays a role in GD3 O-acetylation. However, the mechanisms of ganglioside O-acetylation remain poorly understood. The aim of this study was to determine the involvement of CASD1 in GD2 O-acetylation in breast cancer. The role of CASD1 in OAcGD2 synthesis was first demonstrated using wild type CHO and CHOΔCasd1 cells as cellular models. Overexpression using plasmid transfection and siRNA strategies was used to modulate CASD1 expression in SUM159PT breast cancer cell line. Our results showed that OAcGD2 expression was reduced in SUM159PT that was transiently depleted for CASD1 expression. Additionally, OAcGD2 expression was increased in SUM159PT cells transiently overexpressing CASD1. The modulation of CASD1 expression using transient transfection strategies provided interesting insights into the role of CASD1 in OAcGD2 and OAcGD3 biosynthesis, and it highlights the importance of further studies on O-acetylation mechanisms.

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