Redox Homeostasis and Metabolism in Cancer: A Complex Mechanism and Potential Targeted Therapeutics

Reactive Oxygen Species or “ROS” encompass several molecules derived from oxygen that can oxidize other molecules and subsequently transition rapidly between species. The key roles of ROS in biological processes are cell signaling, biosynthetic processes, and host defense. In cancer cells, increased ROS production and oxidative stress are instigated by carcinogens, oncogenic mutations, and importantly, metabolic reprograming of the rapidly proliferating cancer cells. Increased ROS production activates myriad downstream survival pathways that further cancer progression and metastasis. In this review, we highlight the relation between ROS, the metabolic programing of cancer, and stromal and immune cells with emphasis on and the transcription machinery involved in redox homeostasis, metabolic programing and malignant phenotype. We also shed light on the therapeutic targeting of metabolic pathways generating ROS as we investigate: Orlistat, Biguandes, AICAR, 2 Deoxyglucose, CPI-613, and Etomoxir.

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Mitochondrial Redox Metabolism: The Epicenter of Metabolism during Cancer Progression

Antioxidants ◽

10.3390/antiox10111838 ◽

2021 ◽

Vol 10 (11) ◽

pp. 1838

Author(s):

Feroza K. Choudhury

Keyword(s):

Cancer Cells ◽

Cancer Progression ◽

Redox Homeostasis ◽

Active Role ◽

Redox Status ◽

Metabolic Adaptation ◽

Adaptation To Hypoxia ◽

Central Component ◽

Ros Generation ◽

Redox Metabolism

Mitochondrial redox metabolism is the central component in the cellular metabolic landscape, where anabolic and catabolic pathways are reprogrammed to maintain optimum redox homeostasis. During different stages of cancer, the mitochondrial redox status plays an active role in navigating cancer cells’ progression and regulating metabolic adaptation according to the constraints of each stage. Mitochondrial reactive oxygen species (ROS) accumulation induces malignant transformation. Once vigorous cell proliferation renders the core of the solid tumor hypoxic, the mitochondrial electron transport chain mediates ROS signaling for bringing about cellular adaptation to hypoxia. Highly aggressive cells are selected in this process, which are capable of progressing through the enhanced oxidative stress encountered during different stages of metastasis for distant colonization. Mitochondrial oxidative metabolism is suppressed to lower ROS generation, and the overall cellular metabolism is reprogrammed to maintain the optimum NADPH level in the mitochondria required for redox homeostasis. After reaching the distant organ, the intrinsic metabolic limitations of that organ dictate the success of colonization and flexibility of the mitochondrial metabolism of cancer cells plays a pivotal role in their adaptation to the new environment.

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Synchronization and interaction of proline, ascorbate and oxidative stress pathways under abiotic stress combination in tomato plants

10.1101/2020.06.30.179770 ◽

2020 ◽

Author(s):

María Lopez-Delacalle ◽

Christian J Silva ◽

Teresa C Mestre ◽

Vicente Martinez ◽

Barbara Blanco-Ulate ◽

...

Keyword(s):

Oxidative Stress ◽

Transcription Factors ◽

Metabolic Pathways ◽

Leucine Zipper ◽

Redox Homeostasis ◽

Basic Leucine Zipper ◽

Cellular Redox ◽

Tomato Plants ◽

Leucine Zipper Domain ◽

And Oxidative Stress

ABSTRACTAdverse environmental conditions have a devastating impact on plant productivity. In nature, multiple abiotic stresses occur simultaneously, and plants have evolved unique responses to cope against this combination of stresses. Here, we coupled genome-wide transcriptional profiling and untargeted metabolomics with physiological and biochemical analyses to characterize the effect of salinity and heat applied in combination on the metabolism of tomato plants. Our results demonstrate that this combination of stresses causes a unique reprogramming of metabolic pathways, including changes in the expression of 1,388 genes and the accumulation of 568 molecular features. Pathway enrichment analysis of transcript and metabolite data indicated that the proline and ascorbate pathways act synchronously to maintain cellular redox homeostasis, which was supported by measurements of enzymatic activity and oxidative stress markers. We also identified key transcription factors from the basic Leucine Zipper Domain (bZIP), Zinc Finger Cysteine-2/Histidine-2 (C2H2) and Trihelix families that are likely regulators of the identified up-regulated genes under salinity+heat combination. Our results expand the current understanding of how plants acclimate to environmental stresses in combination and unveils the synergy between key cellular metabolic pathways for effective ROS detoxification. Our study opens the door to elucidating the different signaling mechanisms for stress tolerance.HIGHLIGHTSThe combination of salinity and heat causes a unique reprogramming of tomato metabolic pathways by changing the expression of specific genes and metabolic features.Proline and ascorbate pathways act synchronously to maintain cellular redox homeostasisKey transcription factors from the basic Leucine Zipper Domain (bZIP), Zinc Finger Cysteine-2/Histidine-2 (C2H2) and Trihelix families were identified as putative regulators of the identified up-regulated genes under salinity and heat combination.

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TrxR1, Gsr, and oxidative stress determine hepatocellular carcinoma malignancy

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1903244116 ◽

2019 ◽

Vol 116 (23) ◽

pp. 11408-11417 ◽

Cited By ~ 13

Author(s):

Michael R. McLoughlin ◽

David J. Orlicky ◽

Justin R. Prigge ◽

Pushya Krishna ◽

Emily A. Talago ◽

...

Keyword(s):

Oxidative Stress ◽

Liver Cancer ◽

Cancer Cells ◽

Cancer Progression ◽

Standard Care ◽

Antioxidant Systems ◽

Null Mouse ◽

Dependent Manner ◽

Damage Indices ◽

And Oxidative Stress

Thioredoxin reductase-1 (TrxR1)-, glutathione reductase (Gsr)-, and Nrf2 transcription factor-driven antioxidant systems form an integrated network that combats potentially carcinogenic oxidative damage yet also protects cancer cells from oxidative death. Here we show that although unchallenged wild-type (WT), TrxR1-null, or Gsr-null mouse livers exhibited similarly low DNA damage indices, these were 100-fold higher in unchallenged TrxR1/Gsr–double-null livers. Notwithstanding, spontaneous cancer rates remained surprisingly low in TrxR1/Gsr-null livers. All genotypes, including TrxR1/Gsr-null, were susceptible to N-diethylnitrosamine (DEN)-induced liver cancer, indicating that loss of these antioxidant systems did not prevent cancer cell survival. Interestingly, however, following DEN treatment, TrxR1-null livers developed threefold fewer tumors compared with WT livers. Disruption of TrxR1 in a marked subset of DEN-initiated cancer cells had no effect on their subsequent contributions to tumors, suggesting that TrxR1-disruption does not affect cancer progression under normal care, but does decrease the frequency of DEN-induced cancer initiation. Consistent with this idea, TrxR1-null livers showed altered basal and DEN-exposed metabolomic profiles compared with WT livers. To examine how oxidative stress influenced cancer progression, we compared DEN-induced cancer malignancy under chronically low oxidative stress (TrxR1-null, standard care) vs. elevated oxidative stress (TrxR1/Gsr-null livers, standard care or phenobarbital-exposed TrxR1-null livers). In both cases, elevated oxidative stress was correlated with significantly increased malignancy. Finally, although TrxR1-null and TrxR1/Gsr-null livers showed strong Nrf2 activity in noncancerous hepatocytes, there was no correlation between malignancy and Nrf2 expression within tumors across genotypes. We conclude that TrxR1, Gsr, Nrf2, and oxidative stress are major determinants of liver cancer but in a complex, context-dependent manner.

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Metabolic Regulation of Redox Balance in Cancer

Cancers ◽

10.3390/cancers11070955 ◽

2019 ◽

Vol 11 (7) ◽

pp. 955 ◽

Cited By ~ 25

Author(s):

Vinee Purohit ◽

Diane M. Simeone ◽

Costas A. Lyssiotis

Keyword(s):

Metabolic Pathways ◽

Metabolic Regulation ◽

Redox Homeostasis ◽

Redox Balance ◽

Tumor Evolution ◽

Ros Production ◽

Oxygen Species ◽

Partial Reduction ◽

Dna Mutations

Reactive oxygen species (ROS) are chemically active free radicals produced by partial reduction of oxygen that can activate discrete signaling pathways or disrupt redox homeostasis depending on their concentration. ROS interacts with biomolecules, including DNA, and can cause mutations that can transform normal cells into cancer cells. Furthermore, certain cancer-causing mutations trigger alterations in cellular metabolism that can increase ROS production, resulting in genomic instability, additional DNA mutations, and tumor evolution. To prevent excess ROS-mediated toxicity, cancer-causing mutations concurrently activate pathways that manage this oxidative burden. Hence, an understanding of the metabolic pathways that regulate ROS levels is imperative for devising therapies that target tumor cells. In this review, we summarize the dual role of metabolism as a generator and inhibitor of ROS in cancer and discuss current strategies to target the ROS axis.

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Role of Reductive versus Oxidative Stress in Tumor Progression and Anticancer Drug Resistance

Cells ◽

10.3390/cells10040758 ◽

2021 ◽

Vol 10 (4) ◽

pp. 758

Author(s):

Kyung-Soo Chun ◽

Do-Hee Kim ◽

Young-Joon Surh

Keyword(s):

Cancer Cells ◽

Metabolic Pathways ◽

Redox Homeostasis ◽

Redox Balance ◽

Therapy Resistance ◽

Related Factor ◽

Nuclear Factor ◽

Cellular Redox ◽

Reductive Stress

Redox homeostasis is not only essential for the maintenance of normal physiological functions, but also plays an important role in the growth, survival, and therapy resistance of cancer cells. Altered redox balance and consequent disruption of redox signaling are implicated in the proliferation and progression of cancer cells and their resistance to chemo- and radiotherapy. The nuclear factor erythroid 2 p45-related factor (Nrf2) is the principal stress-responsive transcription factor that plays a pivotal role in maintaining cellular redox homeostasis. Aberrant Nrf2 overactivation has been observed in many cancerous and transformed cells. Uncontrolled amplification of Nrf2-mediated antioxidant signaling results in reductive stress. Some metabolic pathways altered due to reductive stress have been identified as major contributors to tumorigenesis. This review highlights the multifaceted role of reductive stress in cancer development and progression.

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SRC-Family Kinases in Acute Myeloid Leukaemia and Mastocytosis

Cancers ◽

10.3390/cancers12071996 ◽

2020 ◽

Vol 12 (7) ◽

pp. 1996

Author(s):

Edwige Voisset ◽

Fabienne Brenet ◽

Sophie Lopez ◽

Paulo de Sepulveda

Keyword(s):

Cancer Progression ◽

Tyrosine Kinases ◽

Myeloid Leukemia ◽

Cell Transformation ◽

Src Family Kinases ◽

Downstream Signaling ◽

Viral Oncogenes ◽

Oncogenic Mutations ◽

Shed Light ◽

Acute Myeloid

Protein tyrosine kinases have been recognized as important actors of cell transformation and cancer progression, since their discovery as products of viral oncogenes. SRC-family kinases (SFKs) play crucial roles in normal hematopoiesis. Not surprisingly, they are hyperactivated and are essential for membrane receptor downstream signaling in hematological malignancies such as acute myeloid leukemia (AML) and mastocytosis. The precise roles of SFKs are difficult to delineate due to the number of substrates, the functional redundancy among members, and the use of tools that are not selective. Yet, a large num ber of studies have accumulated evidence to support that SFKs are rational therapeutic targets in AML and mastocytosis. These two pathologies are regulated by two related receptor tyrosine kinases, which are well known in the field of hematology: FLT3 and KIT. FLT3 is one of the most frequently mutated genes in AML, while KIT oncogenic mutations occur in 80–90% of mastocytosis. Studies on oncogenic FLT3 and KIT signaling have shed light on specific roles for members of the SFK family. This review highlights the central roles of SFKs in AML and mastocytosis, and their interconnection with FLT3 and KIT oncoproteins.

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Targeting the Redox Landscape in Cancer Therapy

Cancers ◽

10.3390/cancers12071706 ◽

2020 ◽

Vol 12 (7) ◽

pp. 1706 ◽

Cited By ~ 2

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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Generalized Portrait of Cancer Metabolic Pathways Inferred from a List of Genes Overexpressed in Cancer

Genetics Research International ◽

10.1155/2014/646193 ◽

2014 ◽

Vol 2014 ◽

pp. 1-8 ◽

Cited By ~ 3

Author(s):

Eugenia Poliakov ◽

David Managadze ◽

Igor B. Rogozin

Keyword(s):

Cancer Research ◽

Cancer Cells ◽

Cancer Progression ◽

Tumor Suppressors ◽

Metabolic Pathways ◽

Cancer Metabolism ◽

Central Place ◽

Enzymatic Reactions ◽

Kegg Pathways ◽

Different Types

More than half a century from postulated Warburg theory of cancer cells origin, a question of changed metabolism in cancer is again taking the central place. Generalized picture of cancer metabolism was replaced by analysis of signaling and oncogenes in each type of cancer for several decades. However, now empowered with wealth of knowledge about tumor suppressors, oncogenes, and signaling pathways, reprogramming of cellular metabolism (e.g., increased glycolysis to respiration ratio in cancer cells) reemerged as an important element of cancer progression. To analyze level of expression of various proteins including metabolic enzymes across various cancers we used dbEST and Unigene data. We delineated a list of genes that are overexpressed in different types of cancer. We also grouped overexpressed enzymes into KEGG pathways and analyzed adjacent pathways to describe enzymatic reactions that take place in cancer cells and to identify major players that are abundant in cancer protein machinery. Glycolysis/gluconeogenesis and oxidative phosphorylation are the most abundant pathways although several other pathways are enriched in genes from our list. Ubiquitously overexpressed genes could be marked as nonspecific cancer-associated genes when analyzing genes that are overexpressed in certain types of cancer. Thus the list of overexpressed genes may be a useful tool for cancer research.

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Four faces of cellular senescence

The Journal of Cell Biology ◽

10.1083/jcb.201009094 ◽

2011 ◽

Vol 192 (4) ◽

pp. 547-556 ◽

Cited By ~ 1106

Author(s):

Francis Rodier ◽

Judith Campisi

Keyword(s):

Cell Growth ◽

Cancer Cells ◽

Cancer Progression ◽

Cellular Senescence ◽

Tumor Suppression ◽

Tissue Repair ◽

Tumor Promotion ◽

Biological Processes ◽

Opposing Effects ◽

Potential Cancer

Cellular senescence is an important mechanism for preventing the proliferation of potential cancer cells. Recently, however, it has become apparent that this process entails more than a simple cessation of cell growth. In addition to suppressing tumorigenesis, cellular senescence might also promote tissue repair and fuel inflammation associated with aging and cancer progression. Thus, cellular senescence might participate in four complex biological processes (tumor suppression, tumor promotion, aging, and tissue repair), some of which have apparently opposing effects. The challenge now is to understand the senescence response well enough to harness its benefits while suppressing its drawbacks.

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Mesenchymal stem cells alleviate hypoxia-induced oxidative stress and enhance the pro-survival pathways in porcine islets

Experimental Biology and Medicine ◽

10.1177/1535370219844472 ◽

2019 ◽

Vol 244 (9) ◽

pp. 781-788 ◽

Cited By ~ 5

Author(s):

Yixiong Tan ◽

Wei Nie ◽

Cheng Chen ◽

Xuesong He ◽

Yuzhi Xu ◽

...

Keyword(s):

Oxidative Stress ◽

Stem Cells ◽

Cell Death ◽

Mesenchymal Stem Cells ◽

Islet Transplantation ◽

Therapeutic Effects ◽

Ros Production ◽

Survival Pathways ◽

Clinical Islet Transplantation ◽

And Oxidative Stress

Islet transplantation is a promising treatment for selected patients with type 1 diabetes mellitus (T1DM). Hypoxia and oxidative stress are major causes of damage to transplanted islets. Mesenchymal stem cells (MSCs) have been shown to enhance cell survival mainly through paracrine secretion. However, mechanisms of action underlying the protective effects of MSCs on islets have not been fully elucidated. In this study, we investigated whether human umbilical cord-derived MSCs (huc-MSCs) could inhibit hypoxia and ROS-related cell death of neonatal porcine islet cell clusters (NICCs) and further determined the underlying molecular mechanisms. NICCs were cultured in vitro under normoxic and hypoxic (1% O2) conditions with or without MSC-conditioned medium (MSC-CM). Apoptosis of NICCs was evaluated by the AO/EB staining and Annexin V/PI flow cytometry analysis. Total and mitochondrial ROS production was detected by fluorometric assays. Western blot and the ERK pathway inhibitor, PD98059, were used to assess the possible pathways involved. The results showed that MSC-CM suppressed hypoxia-induced oxidative stress and cell death of NICCs. MSC-CM also activated several pro-survival pathways in NICCs under hypoxic conditions. Furthermore, MSC-secreted exosomes and IL-6 partially recapitulated the multifunctional benefits of MSC-CM. This study showed that huc-MSCs protected NICCs from hypoxia-induced cell death by regulating the cell redox state and cell signaling pathways. This increased understanding may enable MSCs to become a more promising adjuvant cell therapy for islet transplantation. Impact statement The utilization of mesenchymal stem cells (MSCs) is a promising approach to serve as adjuvant therapy for islet transplantation. But the inability to translate promising preclinical results into sound therapeutic effects in human subjects indicates a lack of key knowledge of MSC-islet interactions that warrant further research. Hypoxia and oxidative stress are critical factors which lead to a tremendous loss of islet grafts. However, previous studies mainly focused on other aspects of MSC protection such as inducing revascularization, enhancing insulin secretion, and reducing islet apoptosis. In this study, we aim to investigate whether MSC can protect islet cells from hypoxic damage by inhibiting ROS production and the potential underlying pathways involved. We also explore the effects of MSC-derived exosomes and IL-6 on hypoxia-injured islets. Our data provide new molecular targets for developing MSC applications, and this may ultimately promote the efficiency of clinical islet transplantation.

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