scholarly journals Palbociclib and Fulvestrant Act in Synergy to Modulate Central Carbon Metabolism in Breast Cancer Cells

Metabolites ◽  
2019 ◽  
Vol 9 (1) ◽  
pp. 7 ◽  
Author(s):  
Benedikt Warth ◽  
Amelia Palermo ◽  
Nicholas J.W. Rattray ◽  
Nathan V. Lee ◽  
Zhou Zhu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metabolic Pathways ◽  
Cancer Metabolism ◽  
Cell Model ◽  
Cell Metabolism ◽  
Progression Free Survival ◽  
Central Carbon Metabolism ◽  
Pentose Phosphate ◽  
Metabolic Disruption ◽  
Transcriptomic Changes

The aims of this study were to determine whether combination chemotherapeutics exhibit a synergistic effect on breast cancer cell metabolism. Palbociclib, is a selective inhibitor of cyclin-dependent kinases 4 and 6, and when patients are treated in combination with fulvestrant, an estrogen receptor antagonist, they have improved progression-free survival. The mechanisms for this survival advantage are not known. Therefore, we analyzed metabolic and transcriptomic changes in MCF-7 cells following single and combination chemotherapy to determine whether selective metabolic pathways are targeted during these different modes of treatment. Individually, the drugs caused metabolic disruption to the same metabolic pathways, however fulvestrant additionally attenuated the pentose phosphate pathway and the production of important coenzymes. A comprehensive effect was observed when the drugs were applied together, confirming the combinatory therapy’s synergism in the cell model. This study also highlights the power of merging high-dimensional datasets to unravel mechanisms involved in cancer metabolism and therapy.

scholarly journals Oxidative Pentose Phosphate Pathway Enzyme 6-Phosphogluconate Dehydrogenase Plays a Key Role in Breast Cancer Metabolism

Biology ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 85
Author(s):  
Ibrahim H. Polat ◽  
Míriam Tarrado-Castellarnau ◽  
Rohit Bharat ◽  
Jordi Perarnau ◽  
Adrian Benito ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Pentose Phosphate Pathway ◽  
Cancer Metabolism ◽  
Cell Model ◽  
Glucose Consumption ◽  
Redox Balance ◽  
Pentose Phosphate ◽  
Mcf7 Cells ◽  
Mammosphere Formation ◽  
Phosphogluconate Dehydrogenase

The pentose phosphate pathway (PPP) plays an essential role in the metabolism of breast cancer cells for the management of oxidative stress and the synthesis of nucleotides. 6-phosphogluconate dehydrogenase (6PGD) is one of the key enzymes of the oxidative branch of PPP and is involved in nucleotide biosynthesis and redox maintenance status. Here, we aimed to analyze the functional importance of 6PGD in a breast cancer cell model. Inhibition of 6PGD in MCF7 reduced cell proliferation and showed a significant decrease in glucose consumption and an increase in glutamine consumption, resulting in an important alteration in the metabolism of these cells. No difference in reactive oxygen species (ROS) production levels was observed after 6PGD inhibition, indicating that 6PGD, in contrast to glucose 6-phosphate dehydrogenase, is not involved in redox balance. We found that 6PGD inhibition also altered the stem cell characteristics and mammosphere formation capabilities of MCF7 cells, opening new avenues to prevent cancer recurrance after surgery or chemotherapy. Moreover, inhibition of 6PGD via chemical inhibitor S3 resulted in an induction of senescence, which, together with the cell cycle arrest and apoptosis induction, might be orchestrated by p53 activation. Therefore, we postulate 6PGD as a novel therapeutic target to treat breast cancer.

scholarly journals Metabolic Anti-Cancer Effects of Melatonin: Clinically Relevant Prospects

Cancers ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 3018
Author(s):  
Marek Samec ◽  
Alena Liskova ◽  
Lenka Koklesova ◽  
Kevin Zhai ◽  
Elizabeth Varghese ◽  
...  
Keyword(s):  
Cancer Metabolism ◽  
Glucose Transporter ◽  
Aerobic Glycolysis ◽  
Cell Metabolism ◽  
Lactate Production ◽  
Pentose Phosphate ◽  
Metabolic Reprogramming ◽  
Effective Prevention ◽  
Anti Cancer ◽  
Glucose 6 Phosphate Dehydrogenase

Metabolic reprogramming characterized by alterations in nutrient uptake and critical molecular pathways associated with cancer cell metabolism represents a fundamental process of malignant transformation. Melatonin (N-acetyl-5-methoxytryptamine) is a hormone secreted by the pineal gland. Melatonin primarily regulates circadian rhythms but also exerts anti-inflammatory, anti-depressant, antioxidant and anti-tumor activities. Concerning cancer metabolism, melatonin displays significant anticancer effects via the regulation of key components of aerobic glycolysis, gluconeogenesis, the pentose phosphate pathway (PPP) and lipid metabolism. Melatonin treatment affects glucose transporter (GLUT) expression, glucose-6-phosphate dehydrogenase (G6PDH) activity, lactate production and other metabolic contributors. Moreover, melatonin modulates critical players in cancer development, such as HIF-1 and p53. Taken together, melatonin has notable anti-cancer effects at malignancy initiation, progression and metastasing. Further investigations of melatonin impacts relevant for cancer metabolism are expected to create innovative approaches supportive for the effective prevention and targeted therapy of cancers.

scholarly journals KSHV Reprogramming of Host Energy Metabolism for Pathogenesis

2021 ◽  
Vol 11 ◽  
Author(s):  
Xiaoqing Liu ◽  
Caixia Zhu ◽  
Yuyan Wang ◽  
Fang Wei ◽  
Qiliang Cai
Keyword(s):  
Energy Metabolism ◽  
Metabolic Pathways ◽  
B Lymphocyte ◽  
Aerobic Glycolysis ◽  
Cell Metabolism ◽  
Acid Synthesis ◽  
Central Carbon Metabolism ◽  
Central Carbon ◽  
Cell Energy ◽  
Infected Cells

Reprogramming of energy metabolism is a key for cancer development. Kaposi’s sarcoma-associated herpesvirus (KSHV), a human oncogenic herpesvirus, is tightly associated with several human malignancies by infecting B-lymphocyte or endothelial cells. Cancer cell energy metabolism is mainly dominated by three pathways of central carbon metabolism, including aerobic glycolysis, glutaminolysis, and fatty acid synthesis. Increasing evidence has shown that KSHV infection can alter central carbon metabolic pathways to produce biomass for viral replication, as well as the survival and proliferation of infected cells. In this review, we summarize recent studies exploring how KSHV manipulates host cell metabolism to promote viral pathogenesis, which provides the potential therapeutic targets and strategies for KSHV-associated cancers.

scholarly journals Palbociclib and fulvestrant act in synergy to modulate central carbon metabolism in breast cancer cells

2018 ◽  
Author(s):  
Benedikt Warth ◽  
Amelia Palermo ◽  
Nicholas J.W. Rattray ◽  
Nathan V Lee ◽  
Zhou Zhu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Cancer Cells ◽  
Pentose Phosphate Pathway ◽  
Metabolic Pathways ◽  
Breast Cancer Cells ◽  
Pentose Phosphate ◽  
List Type ◽  
Estrogen Receptor Positive ◽  
Positive Breast Cancer

SummaryPalbociclib, is a selective inhibitor of cyclin-dependent kinases 4 and 6 and used as a first-line treatment for patients with estrogen receptor positive breast cancer. It has been shown that patients have improved progression-free survival when treated in combination with fulvestrant, an estrogen receptor antagonist. However, the mechanisms for this survival advantage are not known. We sought to analyze metabolic and transcriptomic changes in MCF-7 adenocarcinoma breast cancer cells following single and combined treatments to determine if selective metabolic pathways are targeted during combination therapy. Our results showed that individually, the drugs caused metabolic disruption to the same metabolic pathways, however fulvestrant additionally attenuated the pentose phosphate pathway and the production of important coenzymes. A comprehensive effect was observed when the drugs were applied together, confirming the combinatory therapy′s synergism in the cell model. This study highlights the power of merging high-dimensional datasets to unravel mechanisms involved in cancer metabolism and therapy.Highlights○First study employing multi-omics to investigate combined therapy on breast cancer cells○Fulvestrant attenuates the pentose phosphate pathway and coenzyme production○Synergism of palbociclib and fulvestrant was confirmed in vitro○Altered key pathways have been identifiedeTOC BlurbJohnson et al. applied an innovative multi-omics approach to decipher metabolic pathways affected by single versus combination dosing of palbociclib and fulvestrant in estrogen receptor positive breast cancer. Key metabolites and genes were correlated within metabolic pathways and shown to be involved in the drugs′ synergism.

scholarly journals Peroxisome Metabolism in Cancer

Cells ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 1692 ◽  
Author(s):  
Jung-Ae Kim
Keyword(s):  
Metabolic Pathways ◽  
Cancer Metabolism ◽  
Cell Metabolism ◽  
Critical Role ◽  
Acid Oxidation ◽  
Metabolic Dysregulation ◽  
Human Disorders ◽  
Peroxisomal Function ◽  
Target Cancer

Peroxisomes are metabolic organelles involved in lipid metabolism and cellular redoxbalance. Peroxisomal function is central to fatty acid oxidation, ether phospholipid synthesis, bile acidsynthesis, and reactive oxygen species homeostasis. Human disorders caused by genetic mutations inperoxisome genes have led to extensive studies on peroxisome biology. Peroxisomal defects are linkedto metabolic dysregulation in diverse human diseases, such as neurodegeneration and age-relateddisorders, revealing the significance of peroxisome metabolism in human health. Cancer is a diseasewith metabolic aberrations. Despite the critical role of peroxisomes in cell metabolism, the functionaleects of peroxisomes in cancer are not as well recognized as those of other metabolic organelles,such as mitochondria. In addition, the significance of peroxisomes in cancer is less appreciated thanit is in degenerative diseases. In this review, I summarize the metabolic pathways in peroxisomesand the dysregulation of peroxisome metabolism in cancer. In addition, I discuss the potential ofinactivating peroxisomes to target cancer metabolism, which may pave the way for more eectivecancer treatment.

scholarly journals Glucose Metabolism and Glucose Transporters in Breast Cancer

2021 ◽  
Vol 9 ◽  
Author(s):  
Eunah Shin ◽  
Ja Seung Koo
Keyword(s):  
Breast Cancer ◽  
Glucose Metabolism ◽  
Stromal Cells ◽  
Warburg Effect ◽  
Molecular Subtype ◽  
Cell Metabolism ◽  
Treatment Strategies ◽  
Glucose Transporters ◽  
Pentose Phosphate ◽  
Cancer Prognosis

Breast cancer is the most common malignancy in women worldwide and is associated with high mortality rates despite the continuously advancing treatment strategies. Glucose is essential for cancer cell metabolism owing to the Warburg effect. During the process of glucose metabolism, various glycolytic metabolites, such as serine and glycine metabolites, are produced and other metabolic pathways, such as the pentose phosphate pathway (PPP), are associated with the process. Glucose is transported into the cell by glucose transporters, such as GLUT. Breast cancer shows high expressions of glucose metabolism-related enzymes and GLUT, which are also related to breast cancer prognosis. Triple negative breast cancer (TNBC), which is a high-grade breast cancer, is especially dependent on glucose metabolism. Breast cancer also harbors various stromal cells such as cancer-associated fibroblasts and immune cells as tumor microenvironment, and there exists a metabolic interaction between these stromal cells and breast cancer cells as explained by the reverse Warburg effect. Breast cancer is heterogeneous, and, consequently, its metabolic status is also diverse, which is especially affected by the molecular subtype, progression stage, and metastatic site. In this review, we will focus on glucose metabolism and glucose transporters in breast cancer, and we will additionally discuss their potential applications as cancer imaging tracers and treatment targets.

scholarly journals Elucidating cancer metabolic plasticity by coupling gene regulation with metabolic pathways

2019 ◽  
Vol 116 (9) ◽  
pp. 3909-3918 ◽  
Author(s):  
Dongya Jia ◽  
Mingyang Lu ◽  
Kwang Hwa Jung ◽  
Jun Hyoung Park ◽  
Linglin Yu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Regulation ◽  
Cancer Cells ◽  
Model Prediction ◽  
Metabolic Pathways ◽  
Cancer Metabolism ◽  
The Cancer Genome Atlas ◽  
Metabolic Phenotype ◽  
Metabolic State ◽  
Metabolic Plasticity

Metabolic plasticity enables cancer cells to switch their metabolism phenotypes between glycolysis and oxidative phosphorylation (OXPHOS) during tumorigenesis and metastasis. However, it is still largely unknown how cancer cells orchestrate gene regulation to balance their glycolysis and OXPHOS activities. Previously, by modeling the gene regulation of cancer metabolism we have reported that cancer cells can acquire a stable hybrid metabolic state in which both glycolysis and OXPHOS can be used. Here, to comprehensively characterize cancer metabolic activity, we establish a theoretical framework by coupling gene regulation with metabolic pathways. Our modeling results demonstrate a direct association between the activities of AMPK and HIF-1, master regulators of OXPHOS and glycolysis, respectively, with the activities of three major metabolic pathways: glucose oxidation, glycolysis, and fatty acid oxidation. Our model further characterizes the hybrid metabolic state and a metabolically inactive state where cells have low activity of both glycolysis and OXPHOS. We verify the model prediction using metabolomics and transcriptomics data from paired tumor and adjacent benign tissue samples from a cohort of breast cancer patients and RNA-sequencing data from The Cancer Genome Atlas. We further validate the model prediction by in vitro studies of aggressive triple-negative breast cancer (TNBC) cells. The experimental results confirm that TNBC cells can maintain a hybrid metabolic phenotype and targeting both glycolysis and OXPHOS is necessary to eliminate their metabolic plasticity. In summary, our work serves as a platform to symmetrically study how tuning gene activity modulates metabolic pathway activity, and vice versa.

scholarly journals Keap1/Nrf2 pathway in the frontiers of cancer and non-cancer cell metabolism

2015 ◽  
Vol 43 (4) ◽  
pp. 639-644 ◽  
Author(s):  
Dionysios V. Chartoumpekis ◽  
Nobunao Wakabayashi ◽  
Thomas W. Kensler
Keyword(s):  
Cancer Cells ◽  
Cancer Cell ◽  
Metabolic Pathways ◽  
De Novo ◽  
Cell Metabolism ◽  
Acid Synthesis ◽  
Pentose Phosphate ◽  
De Novo Lipogenesis ◽  
Nrf2 Pathway ◽  
Cancer Cell Survival

Cancer cells adapt their metabolism to their increased needs for energy and substrates for protein, lipid and nucleic acid synthesis. Nuclear erythroid factor 2-like 2 (Nrf2) pathway is usually activated in cancers and has been suggested to promote cancer cell survival mainly by inducing a large battery of cytoprotective genes. This mini review focuses on metabolic pathways, beyond cytoprotection, which can be directly or indirectly regulated by Nrf2 in cancer cells to affect their survival. The pentose phosphate pathway (PPP) is enhanced by Nrf2 in cancers and aids their growth. PPP has also been found to be up-regulated in non-cancer tissues and other pathways, such as de novo lipogenesis, have been found to be repressed after activation of the Nrf2 pathway. The importance of these Nrf2-regulated metabolic pathways in cancer compared with non-cancer state remains to be determined. Last but not least, the importance of context about Nrf2 and cancer is highlighted as the Nrf2 pathway may be activated in cancers but its pharmacological activators are useful in chemoprevention.

Lighting Up Live-Cell and In Vivo Central Carbon Metabolism with Genetically Encoded Fluorescent Sensors

2020 ◽  
Vol 13 (1) ◽  
pp. 293-314 ◽  
Author(s):  
Zhuo Zhang ◽  
Xiawei Cheng ◽  
Yuzheng Zhao ◽  
Yi Yang
Keyword(s):  
Carbon Metabolism ◽  
Tricarboxylic Acid Cycle ◽  
Cell Metabolism ◽  
Central Carbon Metabolism ◽  
Fluorescent Sensors ◽  
Pentose Phosphate ◽  
Spatiotemporal Information ◽  
Extant Species ◽  
Central Carbon

As the core component of cell metabolism, central carbon metabolism, consisting of glycolysis, the pentose phosphate pathway, and the tricarboxylic acid cycle converts nutrients into metabolic precursors for biomass and energy to sustain the life of virtually all extant species. The metabolite levels or distributions in central carbon metabolism often change dynamically with cell fates, development, and disease progression. However, traditional biochemical methods require cell lysis, making it challenging to obtain spatiotemporal information about metabolites in living cells and in vivo. Genetically encoded fluorescent sensors allow the rapid, sensitive, specific, and real-time readout of metabolite dynamics in living organisms, thereby offering the potential to fill the gap in current techniques. In this review, we introduce recent progress made in the development of genetically encoded fluorescent sensors for central carbon metabolism and discuss their advantages, disadvantages, and applications. Moreover, several future directions of metabolite sensors are also proposed.

Regulatory role of p53 in cancer metabolism through SCO2 and TIGAR in human breast cancer

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e22128-e22128
Author(s):  
S. Choi ◽  
J. Song ◽  
S. Lim ◽  
J. Lee
Keyword(s):  
Breast Cancer ◽  
Cytochrome C ◽  
Cancer Cells ◽  
Cytochrome C Oxidase ◽  
Metabolic Pathways ◽  
Human Breast Cancer ◽  
Cancer Metabolism ◽  
Ductal Carcinoma ◽  
Suppressor Gene ◽  
Human Breast

e22128 Background: Cancer cells showed higher rate of anaerobic respiration than normal cells. The exact mechanisms for this higher rate of glycolysis in cancer cells remain to be elucidated. Recent researches suggest that p53, the most commonly mutated tumor suppressor gene, might play an important roles in the regulation of energy generating metabolic pathways that switch from oxidative phosphorylation to glycolysis through synthesis of cytochrome C oxidase 2 (SCO2) and TP53-induced glycolysis and apoptotic regulator (TIGAR). Methods: We investigated the expression of p53, SCO2, TIGAR and cytochrome C oxidase (COX) in 95 cases of invasive ductal carcinoma using immunohistochemistry. Results: Overexpression of p53, SCO2, TIGAR and COX was observed in 27.4% (26 cases), 82.1% (78 cases), 76.8% (73 cases), and 77.9% (74 cases) respectively. Overexpression of p53 was significantly associated with decreased expression of SCO2 (p=0.009), COX (p=0.001) and TIGAR (p=0.03). Conclusions: These results suggest that p53 can modulate the metabolic pathways via SCO2 and TIGAR in human breast cancer. No significant financial relationships to disclose.

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