scholarly journals Energy and Redox Homeostasis in Tumor Cells

2012 ◽  
Vol 2012 ◽  
pp. 1-15 ◽  
Author(s):  
Marcus Fernandes de Oliveira ◽  
Nívea Dias Amoêdo ◽  
Franklin David Rumjanek
Keyword(s):  
Cancer Cells ◽  
Tumor Cells ◽  
Oxidative Metabolism ◽  
Aerobic Glycolysis ◽  
Redox Homeostasis ◽  
Oxygen Species ◽  
Mitochondrial Fragmentation ◽  
Atp Production ◽  
Antiapoptotic Proteins ◽  
Widespread Belief

Cancer cells display abnormal morphology, chromosomes, and metabolism. This review will focus on the metabolism of tumor cells integrating the available data by way of a functional approach. The first part contains a comprehensive introduction to bioenergetics, mitochondria, and the mechanisms of production and degradation of reactive oxygen species. This will be followed by a discussion on the oxidative metabolism of tumor cells including the morphology, biogenesis, and networking of mitochondria. Tumor cells overexpress proteins that favor fission, such as GTPase dynamin-related protein 1 (Drp1). The interplay between proapoptotic members of the Bcl-2 family that promotes Drp 1-dependent mitochondrial fragmentation and fusogenic antiapoptotic proteins such as Opa-1 will be presented. It will be argued that contrary to the widespread belief that in cancer cells, aerobic glycolysis completely replaces oxidative metabolism, a misrepresentation of Warburg’s original results, mitochondria of tumor cells are fully viable and functional. Cancer cells also carry out oxidative metabolism and generally conform to the orthodox model of ATP production maintaining as well an intact electron transport system. Finally, data will be presented indicating that the key to tumor cell survival in an ROS rich environment depends on the overexpression of antioxidant enzymes and high levels of the nonenzymatic antioxidant scavengers.

scholarly journals Oxidative Stress in the Tumor Microenvironment and Its Relevance to Cancer Immunotherapy

Cancers ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 986
Author(s):  
Nada S. Aboelella ◽  
Caitlin Brandle ◽  
Timothy Kim ◽  
Zhi-Chun Ding ◽  
Gang Zhou
Keyword(s):  
Oxidative Stress ◽  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Redox Homeostasis ◽  
Tumor Rejection ◽  
Oxygen Species ◽  
Antitumor Effects ◽  
Key Drivers ◽  
Cancer Immunotherapies ◽  
The Impact

It has been well-established that cancer cells are under constant oxidative stress, as reflected by elevated basal level of reactive oxygen species (ROS), due to increased metabolism driven by aberrant cell growth. Cancer cells can adapt to maintain redox homeostasis through a variety of mechanisms. The prevalent perception about ROS is that they are one of the key drivers promoting tumor initiation, progression, metastasis, and drug resistance. Based on this notion, numerous antioxidants that aim to mitigate tumor oxidative stress have been tested for cancer prevention or treatment, although the effectiveness of this strategy has yet to be established. In recent years, it has been increasingly appreciated that ROS have a complex, multifaceted role in the tumor microenvironment (TME), and that tumor redox can be targeted to amplify oxidative stress inside the tumor to cause tumor destruction. Accumulating evidence indicates that cancer immunotherapies can alter tumor redox to intensify tumor oxidative stress, resulting in ROS-dependent tumor rejection. Herein we review the recent progresses regarding the impact of ROS on cancer cells and various immune cells in the TME, and discuss the emerging ROS-modulating strategies that can be used in combination with cancer immunotherapies to achieve enhanced antitumor effects.

scholarly journals Mitochondria Targeting as an Effective Strategy for Cancer Therapy

2020 ◽  
Vol 21 (9) ◽  
pp. 3363 ◽  
Author(s):  
Poorva Ghosh ◽  
Chantal Vidal ◽  
Sanchareeka Dey ◽  
Li Zhang
Keyword(s):  
Cancer Therapy ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Mitochondrial Respiration ◽  
Mitochondrial Dynamics ◽  
Metastatic Tumor ◽  
Atp Production ◽  
Development Of Resistance ◽  
Mitochondrial Alterations ◽  
Mitochondria Targeting

Mitochondria are well known for their role in ATP production and biosynthesis of macromolecules. Importantly, increasing experimental evidence points to the roles of mitochondrial bioenergetics, dynamics, and signaling in tumorigenesis. Recent studies have shown that many types of cancer cells, including metastatic tumor cells, therapy-resistant tumor cells, and cancer stem cells, are reliant on mitochondrial respiration, and upregulate oxidative phosphorylation (OXPHOS) activity to fuel tumorigenesis. Mitochondrial metabolism is crucial for tumor proliferation, tumor survival, and metastasis. Mitochondrial OXPHOS dependency of cancer has been shown to underlie the development of resistance to chemotherapy and radiotherapy. Furthermore, recent studies have demonstrated that elevated heme synthesis and uptake leads to intensified mitochondrial respiration and ATP generation, thereby promoting tumorigenic functions in non-small cell lung cancer (NSCLC) cells. Also, lowering heme uptake/synthesis inhibits mitochondrial OXPHOS and effectively reduces oxygen consumption, thereby inhibiting cancer cell proliferation, migration, and tumor growth in NSCLC. Besides metabolic changes, mitochondrial dynamics such as fission and fusion are also altered in cancer cells. These alterations render mitochondria a vulnerable target for cancer therapy. This review summarizes recent advances in the understanding of mitochondrial alterations in cancer cells that contribute to tumorigenesis and the development of drug resistance. It highlights novel approaches involving mitochondria targeting in cancer therapy.

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 Differential Mechanism of ATP Production Occurs in Response to Succinylacetone in Colon Cancer Cells

Molecules ◽  
2019 ◽  
Vol 24 (19) ◽  
pp. 3575 ◽  
Author(s):  
Lee ◽  
Woo ◽  
Yoo ◽  
Cho ◽  
Kim
Keyword(s):  
Reactive Oxygen Species ◽  
Colon Cancer ◽  
Cancer Cells ◽  
Pyruvate Dehydrogenase ◽  
Oxygen Species ◽  
Colon Cancer Cells ◽  
Atp Production ◽  
Ht29 Cells ◽  
Differential Mechanism ◽  
Hct116 Cells

Our aim was to verify the potential ability of succinylacetone (SA) to inhibit mitochondrial function, thereby suppressing cancer cell proliferation. SA treatment caused apoptosis in HCT116 and HT29 cells, but not in SW480 cells, with mitochondria playing a key role. We checked for dysfunctional mitochondria after SA treatment. Mitochondria of HT29 cells were swollen, indicating damage, whereas in HCT116 cells, several mitochondria had a diminished size. Damaged mitochondria decreased ATP production and induced reactive oxygen species (ROS) in the cells. To understand SA-induced reduction in ATP production, we investigated the electron transfer chains (ETC) and pyruvate dehydrogenase kinase (PDK) activity, which prevents the transfer of acetyl-CoA to the TCA (tricarboxylic acid) cycle by inhibiting PDH (pyruvate dehydrogenase) activity. In each cell line, the inhibitory mechanism of ATP by SA was different. The activity of complex III consisting of the mitochondrial ETCs in HT29 cells was decreased. In contrast, PDH activity in HCT116 cells was reduced. Nicotinamide nucleotide transhydrogenase (NNT)-removing reactive oxygen species (ROS) was upregulated in HT29 cells, but not in HCT116 cells, indicating that in HT29 cells, a defense mechanism was activated against ROS. Collectively, our study showed a differential mechanism occurs in response to SA in colon cancer cells.

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.

The Tangled Mitochondrial Metabolism in Cancer: An Innovative Pharmacological Approach

2020 ◽  
Vol 27 (13) ◽  
pp. 2106-2117 ◽  
Author(s):  
Patrizia Bottoni ◽  
Roberto Scatena
Keyword(s):  
Reactive Oxygen Species ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Cancer Progression ◽  
Oxidative Metabolism ◽  
Reactive Oxygen ◽  
Mitochondrial Metabolism ◽  
Oxygen Species ◽  
Therapeutic Approaches ◽  
Fundamental Step

Background: Mitochondria are remarkably gaining significant and different pathogenic roles in cancer (i.e., to sustain specific metabolism, to activate signaling pathways, to promote apoptosis resistance, to favor cancer cell dissemination, and finally to facilitate genome instability). Interestingly, all these roles seem to be linked to the fundamental activity of mitochondria, i.e. oxidative metabolism. Intriguingly, a typical modification of mitochondrial oxidative metabolism and reactive oxygen species production/ neutralization seems to have a central role in all these tangled pathogenic roles in cancer. On these bases, a careful understanding of the molecular relationships between cancer and mitochondria may represent a fundamental step to realize therapeutic approaches blocking the typical cancer progression. The main aim of this review is to stress some neglected aspects of oxidative mitochondrial metabolism of cancer cells to promote more translational research with diagnostic and therapeutic potential. Methods: We reviewed the available literature regarding clinical and experimental studies on various roles of mitochondria in cancer, with attention to the cancer cell mitochondrial metabolism. Results: Mitochondria are an important source of reactive oxygen species. Their toxic effects seem to increase in cancer cells. However, it is not clear if damage depends on ROS overproduction and/or defect in detoxification. Failure of both these processes is likely a critical component of the cancer process and is strictly related to the actual microenvironment of cancer cells. Conclusions: Mitochondria, also by ROS production, have a fundamental pathogenetic role in promoting and maintaining cancer and its spreading. To carefully understand the tangled redox state of cancer cells mitochondria represents a fundamental step to realize therapeutic approaches blocking the typical cancer progression.

scholarly journals Cyclooxygenase-2-Mediated Up-Regulation of Mitochondrial Transcription Factor A Mitigates the Radio-Sensitivity of Cancer Cells

2019 ◽  
Vol 20 (5) ◽  
pp. 1218 ◽  
Author(s):  
Fan Tang ◽  
Rui Zhang ◽  
Jun Wang
Keyword(s):  
Transcription Factor ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Cyclooxygenase 2 ◽  
Mitochondrial Fragmentation ◽  
Mitochondrial Transcription ◽  
Mitochondrial Transcription Factor ◽  
Radiation Induced ◽  
Mitochondrial Transcription Factor A ◽  
Cox 2

Mitochondrial transcription factor A (TFAM) regulates mitochondrial biogenesis, and it is a candidate target for sensitizing tumor during therapy. Previous studies identified that increased TFAM expression conferred tumor cells resistance to ionizing radiation. However, the mechanisms on how TFAM are regulated in irradiated tumor cells remain to be explored. In this research, we demonstrated the contribution of cyclooxygenase-2 (COX-2) to enhancing TFAM expression in irradiated tumor cells. Our results showed TFAM was concomitantly up-regulated with COX-2 in irradiated tumor cells. Inhibition of COX-2 by NS-398 blocked radiation-induced expression of TFAM, and prostaglandin E2 (PGE2) treatment stimulated TFAM expression. We next provided evidence that DRP1-mediated mitochondrial fragmentation was a reason for TFAM up-regulation in irradiated cells, by using small interfering RNA (siRNA) and selective inhibitor-targeted DRP1. Furthermore, we proved that p38-MAPK-connected COX-2, and DRP1-mediated TFAM up-regulation. Enhanced phosphorylation of p38 in irradiated tumor cells promoted DRP1 expression, mitochondrial fragmentation, and TFAM expression. NS-398 treatment inhibited radiation-induced p38 phosphorylation, while PGE2 stimulated the activation of p38. The results put forward a mechanism where COX-2 stimulates TFAM expression via p38-mediated DRP1/mitochondrial fragmentation signaling in irradiated tumor cells, which may be of value in understanding how to sensitize cancer cells during radiotherapy.

scholarly journals Cancer metabolism and intervention therapy

2021 ◽  
Vol 2 (1) ◽  
Author(s):  
Huakan Zhao ◽  
Yongsheng Li
Keyword(s):  
Cancer Cells ◽  
Tumor Cells ◽  
Cancer Metabolism ◽  
Aerobic Glycolysis ◽  
Acid Synthesis ◽  
Pentose Phosphate ◽  
Metabolic Reprogramming ◽  
Cancer Therapies ◽  
Proliferation And Metastasis ◽  
Immunosuppressive Microenvironment

AbstractMetabolic reprogramming with heterogeneity is a hallmark of cancer and is at the basis of malignant behaviors. It supports the proliferation and metastasis of tumor cells according to the low nutrition and hypoxic microenvironment. Tumor cells frantically grab energy sources (such as glucose, fatty acids, and glutamine) from different pathways to produce a variety of biomass to meet their material needs via enhanced synthetic pathways, including aerobic glycolysis, glutaminolysis, fatty acid synthesis (FAS), and pentose phosphate pathway (PPP). To survive from stress conditions (e.g., metastasis, irradiation, or chemotherapy), tumor cells have to reprogram their metabolism from biomass production towards the generation of abundant adenosine triphosphate (ATP) and antioxidants. In addition, cancer cells remodel the microenvironment through metabolites, promoting an immunosuppressive microenvironment. Herein, we discuss how the metabolism is reprogrammed in cancer cells and how the tumor microenvironment is educated via the metabolic products. We also highlight potential metabolic targets for cancer therapies.

scholarly journals The Crosstalk Between Cell Adhesion and Cancer Metabolism

2019 ◽  
Vol 20 (8) ◽  
pp. 1933 ◽  
Author(s):  
Bárbara Sousa ◽  
Joana Pereira ◽  
Joana Paredes
Keyword(s):  
Cell Adhesion ◽  
Cancer Cells ◽  
Cancer Metabolism ◽  
Aerobic Glycolysis ◽  
Redox Homeostasis ◽  
Building Blocks ◽  
Metabolic Reprogramming ◽  
Special Focus ◽  
Oncogenic Signaling ◽  
Cell Cell

Cancer cells preferentially use aerobic glycolysis over mitochondria oxidative phosphorylation for energy production, and this metabolic reprogramming is currently recognized as a hallmark of cancer. Oncogenic signaling frequently converges with this metabolic shift, increasing cancer cells’ ability to produce building blocks and energy, as well as to maintain redox homeostasis. Alterations in cell–cell and cell–extracellular matrix (ECM) adhesion promote cancer cell invasion, intravasation, anchorage-independent survival in circulation, and extravasation, as well as homing in a distant organ. Importantly, during this multi-step metastatic process, cells need to induce metabolic rewiring, in order to produce the energy needed, as well as to impair oxidative stress. Although the individual implications of adhesion molecules and metabolic reprogramming in cancer have been widely explored over the years, the crosstalk between cell adhesion molecular machinery and metabolic pathways is far from being clearly understood, in both normal and cancer contexts. This review summarizes our understanding about the influence of cell–cell and cell–matrix adhesion in the metabolic behavior of cancer cells, with a special focus concerning the role of classical cadherins, such as Epithelial (E)-cadherin and Placental (P)-cadherin.

scholarly journals Targeting the Redox Landscape in Cancer Therapy

Cancers ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 1706 ◽  
Author(s):  
Dilip Narayanan ◽  
Sana Ma ◽  
Dennis Özcelik
Keyword(s):  
Cancer Therapy ◽  
Cancer Cells ◽  
Redox Homeostasis ◽  
Tumor Development ◽  
Cellular Level ◽  
Ros Production ◽  
Oxygen Species ◽  
Detoxifying Enzymes ◽  
Transport Chain ◽  
Hypoxic Tumor

Reactive oxygen species (ROS) are produced predominantly by the mitochondrial electron transport chain and by NADPH oxidases in peroxisomes and in the endoplasmic reticulum. The antioxidative defense counters overproduction of ROS with detoxifying enzymes and molecular scavengers, for instance, superoxide dismutase and glutathione, in order to restore redox homeostasis. Mutations in the redox landscape can induce carcinogenesis, whereas increased ROS production can perpetuate cancer development. Moreover, cancer cells can increase production of antioxidants, leading to resistance against chemo- or radiotherapy. Research has been developing pharmaceuticals to target the redox landscape in cancer. For instance, inhibition of key players in the redox landscape aims to modulate ROS production in order to prevent tumor development or to sensitize cancer cells in radiotherapy. Besides the redox landscape of a single cell, alternative strategies take aim at the multi-cellular level. Extracellular vesicles, such as exosomes, are crucial for the development of the hypoxic tumor microenvironment, and hence are explored as target and as drug delivery systems in cancer therapy. This review summarizes the current pharmaceutical and experimental interventions of the cancer redox landscape.

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