scholarly journals Phytochemicals Block Glucose Utilization and Lipid Synthesis to Counteract Metabolic Reprogramming in Cancer Cells

2021 ◽  
Vol 11 (3) ◽  
pp. 1259
Author(s):  
Qiong Wu ◽  
Bo Zhao ◽  
Guangchao Sui ◽  
Jinming Shi
Keyword(s):  
Cancer Cells ◽  
Metabolic Pathways ◽  
De Novo ◽  
Aerobic Glycolysis ◽  
Structural Characteristics ◽  
Natural Compounds ◽  
Metabolic Reprogramming ◽  
De Novo Lipogenesis ◽  
Anticancer Activities ◽  
Substrate Analogs

Aberrant metabolism is one of the hallmarks of cancers. The contributions of dysregulated metabolism to cancer development, such as tumor cell survival, metastasis and drug resistance, have been extensively characterized. “Reprogrammed” metabolic pathways in cancer cells are mainly represented by excessive glucose consumption and hyperactive de novo lipogenesis. Natural compounds with anticancer activities are constantly being demonstrated to target metabolic processes, such as glucose transport, aerobic glycolysis, fatty acid synthesis and desaturation. However, their molecular targets and underlying anticancer mechanisms remain largely unclear or controversial. Mounting evidence indicated that these natural compounds could modulate the expression of key regulatory enzymes in various metabolic pathways at transcriptional and translational levels. Meanwhile, natural compounds could also inhibit the activities of these enzymes by acting as substrate analogs or altering their protein conformations. The actions of natural compounds in the crosstalk between metabolism modulation and cancer cell destiny have become increasingly attractive. In this review, we summarize the activities of natural small molecules in inhibiting key enzymes of metabolic pathways. We illustrate the structural characteristics of these compounds at the molecular level as either inhibitor of various enzymes or regulators of metabolic pathways in cancer cells. Our ultimate goal is to both facilitate the clinical application of natural compounds in cancer therapies and promote the development of novel anticancer therapeutics.

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.

scholarly journals Metabolic Reprogramming of Thyroid Cancer Cells and Crosstalk in Their Microenvironment

2021 ◽  
Vol 11 ◽  
Author(s):  
Lisha Bao ◽  
Tong Xu ◽  
Xixuan Lu ◽  
Ping Huang ◽  
Zongfu Pan ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Cancer Cells ◽  
Tumor Cells ◽  
De Novo ◽  
Aerobic Glycolysis ◽  
Lipid Synthesis ◽  
Acid Synthesis ◽  
Tumor Formation ◽  
Metabolic Reprogramming ◽  
Normal Cells

Metabolism differs significantly between tumor and normal cells. Metabolic reprogramming in cancer cells and metabolic interplay in the tumor microenvironment (TME) are important for tumor formation and progression. Tumor cells show changes in both catabolism and anabolism. Altered aerobic glycolysis, known as the Warburg effect, is a well-recognized characteristic of tumor cell energy metabolism. Compared with normal cells, tumor cells consume more glucose and glutamine. The enhanced anabolism in tumor cells includes de novo lipid synthesis as well as protein and nucleic acid synthesis. Although these forms of energy supply are uneconomical, they are required for the functioning of cancer cells, including those in thyroid cancer (TC). Increasing attention has recently focused on alterations of the TME. Understanding the metabolic changes governing the intricate relationship between TC cells and the TME may provide novel ideas for the treatment of TC.

Untangling the Metabolic Reprogramming in Brain Cancer: Discovering Key Molecular Players Using Mass Spectrometry

2019 ◽  
Vol 19 (17) ◽  
pp. 1521-1534 ◽  
Author(s):  
Anatoly Sorokin ◽  
Vsevolod Shurkhay ◽  
Stanislav Pekov ◽  
Evgeny Zhvansky ◽  
Daniil Ivanov ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Brain Cancer ◽  
De Novo ◽  
Aerobic Glycolysis ◽  
Lipid Production ◽  
Dietary Fatty Acids ◽  
Metabolic Reprogramming ◽  
Detection Methods ◽  
Malignant Cells ◽  
Proliferating Cells

Cells metabolism alteration is the new hallmark of cancer, as well as an important method for carcinogenesis investigation. It is well known that the malignant cells switch to aerobic glycolysis pathway occurring also in healthy proliferating cells. Recently, it was shown that in malignant cells de novo synthesis of the intracellular fatty acid replaces dietary fatty acids which change the lipid composition of cancer cells noticeably. These alterations in energy metabolism and structural lipid production explain the high proliferation rate of malignant tissues. However, metabolic reprogramming affects not only lipid metabolism but many of the metabolic pathways in the cell. 2-hydroxyglutarate was considered as cancer cell biomarker and its presence is associated with oxidative stress influencing the mitochondria functions. Among the variety of metabolite detection methods, mass spectrometry stands out as the most effective method for simultaneous identification and quantification of the metabolites. As the metabolic reprogramming is tightly connected with epigenetics and signaling modifications, the evaluation of metabolite alterations in cells is a promising approach to investigate the carcinogenesis which is necessary for improving current diagnostic capabilities and therapeutic capabilities. In this paper, we overview recent studies on metabolic alteration and oncometabolites, especially concerning brain cancer and mass spectrometry approaches which are now in use for the investigation of the metabolic pathway.

The F1Fo-ATPase inhibitor, IF1, is a critical regulator of energy metabolism in cancer cells

2021 ◽  
Vol 49 (2) ◽  
pp. 815-827
Author(s):  
Giancarlo Solaini ◽  
Gianluca Sgarbi ◽  
Alessandra Baracca
Keyword(s):  
Cancer Cells ◽  
Atp Synthase ◽  
Aerobic Glycolysis ◽  
Cell Metabolism ◽  
Metabolic Reprogramming ◽  
Endogenous Inhibitor ◽  
Atpase Inhibitor ◽  
Molecular Action ◽  
F1fo Atpase

In the last two decades, IF1, the endogenous inhibitor of the mitochondrial F1Fo-ATPase (ATP synthase) has assumed greater and ever greater interest since it has been found to be overexpressed in many cancers. At present, several findings indicate that IF1 is capable of playing a central role in cancer cells by promoting metabolic reprogramming, proliferation and resistance to cell death. However, the mechanism(s) at the basis of this pro-oncogenic action of IF1 remains elusive. Here, we recall the main features of the mechanism of the action of IF1 when the ATP synthase works in reverse, and discuss the experimental evidence that support its relevance in cancer cells. In particular, a clear pro-oncogenic action of IF1 is to avoid wasting of ATP when cancer cells are exposed to anoxia or near anoxia conditions, therefore favoring cell survival and tumor growth. However, more recently, various papers have described IF1 as an inhibitor of the ATP synthase when it is working physiologically (i.e. synthethizing ATP), and therefore reprogramming cell metabolism to aerobic glycolysis. In contrast, other studies excluded IF1 as an inhibitor of ATP synthase under normoxia, providing the basis for a hot debate. This review focuses on the role of IF1 as a modulator of the ATP synthase in normoxic cancer cells with the awareness that the knowledge of the molecular action of IF1 on the ATP synthase is crucial in unravelling the molecular mechanism(s) responsible for the pro-oncogenic role of IF1 in cancer and in developing related anticancer strategies.

scholarly journals A Novel Therapeutic Target, BACH1, Regulates Cancer Metabolism

2021 ◽  
Author(s):  
Jiyoung Lee ◽  
Joselyn Padilla
Keyword(s):  
Cancer Cells ◽  
Cancer Patients ◽  
Transcriptional Activation ◽  
Pyruvate Dehydrogenase ◽  
Therapeutic Target ◽  
Metabolic Pathways ◽  
Cancer Metabolism ◽  
Aerobic Glycolysis ◽  
Pyruvate Dehydrogenase Kinase ◽  
Migration And Invasion

BTB domain and CNC homology 1 (BACH1) is a highly expressed transcription factor in tumors including breast and lung, relative to their non-tumor tissues. BACH1 is known to regulate multiple physiological processes including heme homeostasis, oxidative stress response, senescence, cell cycle, and mitosis. In a tumor, BACH1 promotes invasion and metastasis of cancer cells, and the expression of BACH1 presents a poor outcome for cancer patients including breast cancer patients. Recent studies identified novel functional roles of BACH1 in the regulation of metabolic pathways in cancer cells. BACH1 inhibits mitochondrial metabolism through transcriptional suppression of mitochondrial membrane genes. In addition, BACH1 suppresses activity of pyruvate dehydrogenase (PDH), a key enzyme that converts pyruvate to acetyl-CoA for the citric acid (TCA) cycle through transcriptional activation of pyruvate dehydrogenase kinase (PDK). Moreover, BACH1 increases glucose uptake and lactate secretion in aerobic glycolysis through the expression of metabolic enzymes involved such as hexokinase 2 (HK2) and glyceraldehyde 3- phosphate dehydrogenase (GAPDH). Pharmacological or genetic inhibition of BACH1 could reprogramme metabolic pathways, subsequently rendering metabolic vulnerability of cancer cells. Furthermore, inhibition of BACH1 decreased antioxidant-induced glycolysis rates as well as reduced migration and invasion of cancer cells, suggesting BACH1 as a potentially useful cancer therapeutic target.

scholarly journals Interaction between CD36 and FABP4 modulates adipocyte-induced fatty acid import and metabolism in breast cancer

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Jones Gyamfi ◽  
Joo Hye Yeo ◽  
Doru Kwon ◽  
Byung Soh Min ◽  
Yoon Jin Cha ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Fatty Acid ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Tumour Microenvironment ◽  
Metabolic Reprogramming ◽  
De Novo Lipogenesis ◽  
Mesenchymal Transition ◽  
Genetic Ablation ◽  
Cd36 Expression

AbstractAdipocytes influence breast cancer behaviour via fatty acid release into the tumour microenvironment. Co-culturing human adipocytes and breast cancer cells increased CD36 expression, with fatty acid import into breast cancer cells. Genetic ablation of CD36 attenuates adipocyte-induced epithelial-mesenchymal transition (EMT) and stemness. We show a feedforward loop between CD36 and STAT3; where CD36 activates STAT3 signalling and STAT3 binds to the CD36 promoter, regulating its expression. CD36 expression results in metabolic reprogramming, with a shift towards fatty acid oxidation. CD36 inhibition induces de novo lipogenesis in breast cancer cells. Increased CD36 expression occurs with increased FABP4 expression. We showed that CD36 directly interacts with FABP4 to regulate fatty acid import, transport, and metabolism. CD36 and FABP4 inhibition induces apoptosis in tumour cells. These results indicate that CD36 mediates fatty acid import from adipocytes into cancer cells and activates signalling pathways that drive tumour progression. Targeting CD36 may have a potential for therapy, which will target the tumour microenvironment.

scholarly journals Metabolic Reprogramming from Glycolysis to Fatty Acid Uptake and beta-Oxidation in Platinum-Resistant Cancer Cells

2021 ◽  
Author(s):  
Junjie Li ◽  
Yuying Tan ◽  
Guangyuan Zhao ◽  
Kai-Chih Huang ◽  
Horacio Cardenas ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Fatty Acid ◽  
Single Cell ◽  
Cancer Cell ◽  
Aerobic Glycolysis ◽  
Fatty Acid Uptake ◽  
Metabolic Reprogramming ◽  
De Novo Lipogenesis ◽  
Acid Uptake ◽  
Beta Oxidation

Increased aerobic glycolysis is widely considered as a hallmark of cancer. Yet, cancer cell metabolic reprograming during development of therapeutic resistance is under-studied. Here, through high-throughput stimulated Raman scattering imaging and single cell analysis, we found that cisplatin-resistant cells exhibit increased uptake of exogenous fatty acids, accompanied with decreased glucose uptake and de novo lipogenesis, indicating a reprogramming from glucose and glycolysis dependent to fatty acid uptake and beta-oxidation dependent anabolic and energy metabolism. A metabolic index incorporating measurements of glucose derived anabolism and fatty acid uptake correlates linearly to the level of resistance to cisplatin in ovarian cancer cell lines and in primary cells isolated from ovarian cancer patients. Mechanistically, the increased fatty acid uptake facilitates cancer cell survival under cisplatin-induced oxidative stress by enhancing energy production through beta-oxidation. Consequently, blocking fatty acid beta-oxidation by a small molecule inhibitor in combination with cisplatin or carboplatin synergistically suppressed ovarian cancer proliferation in vitro and growth of patient-derived xenograft in vivo. Collectively, these findings support a new way for rapid detection of cisplatin-resistance at single cell level and a new strategy for treatment of cisplatin-resistant tumors.

scholarly journals Targeting Cancer Metabolism to Resensitize Chemotherapy: Potential Development of Cancer Chemosensitizers from Traditional Chinese Medicines

Cancers ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 404 ◽  
Author(s):  
Guo ◽  
Tan ◽  
Chen ◽  
Wang ◽  
Feng
Keyword(s):  
Chinese Medicine ◽  
Cancer Therapy ◽  
Traditional Chinese Medicine ◽  
Cancer Cells ◽  
Metabolic Pathways ◽  
Cancer Metabolism ◽  
Metabolic Reprogramming ◽  
Traditional Chinese Medicines ◽  
Chinese Medicines ◽  
Incidence And Mortality

Cancer is a common and complex disease with high incidence and mortality rates, which causes a severe public health problem worldwide. As one of the standard therapeutic approaches for cancer therapy, the prognosis and outcome of chemotherapy are still far from satisfactory due to the severe side effects and increasingly acquired resistance. The development of novel and effective treatment strategies to overcome chemoresistance is urgent for cancer therapy. Metabolic reprogramming is one of the hallmarks of cancer. Cancer cells could rewire metabolic pathways to facilitate tumorigenesis, tumor progression, and metastasis, as well as chemoresistance. The metabolic reprogramming may serve as a promising therapeutic strategy and rekindle the research enthusiasm for overcoming chemoresistance. This review focuses on emerging mechanisms underlying rewired metabolic pathways for cancer chemoresistance in terms of glucose and energy, lipid, amino acid, and nucleotide metabolisms, as well as other related metabolisms. In particular, we highlight the potential of traditional Chinese medicine as a chemosensitizer for cancer chemotherapy from the metabolic perspective. The perspectives of metabolic targeting to chemoresistance are also discussed. In conclusion, the elucidation of the underlying metabolic reprogramming mechanisms by which cancer cells develop chemoresistance and traditional Chinese medicines resensitize chemotherapy would provide us a new insight into developing promising therapeutics and scientific evidence for clinical use of traditional Chinese medicine as a chemosensitizer for cancer therapy.

scholarly journals Metabolic Constants and Plasticity of Cancer Cells in a Limiting Glucose and Glutamine Microenvironment—A Pyruvate Perspective

2020 ◽  
Vol 10 ◽  
Author(s):  
Angela M. Otto
Keyword(s):  
Cancer Cells ◽  
Metabolic Network ◽  
Metabolic Pathways ◽  
Cancer Cell Line ◽  
Tca Cycle ◽  
Reaction Rates ◽  
Diagnostic Methods ◽  
Metabolic Reprogramming ◽  
Amino Acid Synthesis ◽  
The Tca Cycle

The metabolism of cancer cells is an issue of dealing with fluctuating and limiting levels of nutrients in a precarious microenvironment to ensure their vitality and propagation. Glucose and glutamine are central metabolites for catabolic and anabolic metabolism, which is in the limelight of numerous diagnostic methods and therapeutic targeting. Understanding tumor metabolism in conditions of nutrient depletion is important for such applications and for interpreting the readouts. To exemplify the metabolic network of tumor cells in a model system, the fate 13C6-glucose was tracked in a breast cancer cell line growing in variable low glucose/low glutamine conditions. 13C-glucose-derived metabolites allowed to deduce the engagement of metabolic pathways, namely glycolysis, the TCA-cycle including glutamine and pyruvate anaplerosis, amino acid synthesis (serine, glycine, aspartate, glutamate), gluconeogenesis, and pyruvate replenishment. While the metabolic program did not change, limiting glucose and glutamine supply reduced cellular metabolite levels and enhanced pyruvate recycling as well as pyruvate carboxylation for entry into the TCA-cycle. Otherwise, the same metabolic pathways, including gluconeogenesis, were similarly engaged with physiologically saturating as with limiting glucose and glutamine. Therefore, the metabolic plasticity in precarious nutritional microenvironment does not require metabolic reprogramming, but is based on dynamic changes in metabolite quantity, reaction rates, and directions of the existing metabolic network.

scholarly journals Oncogenic KRAS Drives Metabolic Vulnerabilities by Directly Regulating Metabolic Enzymes in Cancer

2020 ◽  
Vol 07 (01) ◽  
pp. 001-002
Author(s):  
Liyi Zhang
Keyword(s):  
Cancer Cells ◽  
Splice Variants ◽  
Human Cancer ◽  
Aerobic Glycolysis ◽  
Metabolic Enzymes ◽  
Glycolytic Enzyme ◽  
Metabolic Reprogramming ◽  
Functional Differences ◽  
Oncogenic Mutations ◽  
Novel Therapeutic Strategies

AbstractMetabolic reprogramming, such as enhanced aerobic glycolysis, allows cancer cells to maintain viability and promote proliferation. It is one of the major consequences of oncogenic mutations. KRAS is the most frequently mutated oncogene in human cancer. It is thought to be closely related to metabolic reprogramming. However, it is not clear whether it can participate in metabolic reprogramming by directly regulating metabolic enzymes. Additionally, the functional differences among the splice variants of KRAS have not been determined. In a study, recently published in Nature, Amendola et al reported a unique interaction between one of the KRAS splice variants (KRAS4A) and the major glycolytic enzyme (hexokinase 1) in cancer cells. Their findings indicated that a better understanding on the regulation of hexokinase 1 by KRAS may reveal novel therapeutic strategies.

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