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Journal Article•DOI•

ROS homeostasis and metabolism: a dangerous liason in cancer cells.

Emiliano Panieri1, Massimo Santoro1, Massimo Santoro2•
University of Turin1, Katholieke Universiteit Leuven2
09 Jun 2016-Cell Death and Disease (Nature Publishing Group)-Vol. 7, Iss: 6, pp 0
TL;DR: How the mitochondria has a key role in regulating the interplay between redox homeostasis and metabolism within tumor cells is described, and the potential therapeutic use of agents that directly or indirectly block metabolism is discussed.
Abstract: Tumor cells harbor genetic alterations that promote a continuous and elevated production of reactive oxygen species. Whereas such oxidative stress conditions would be harmful to normal cells, they facilitate tumor growth in multiple ways by causing DNA damage and genomic instability, and ultimately, by reprogramming cancer cell metabolism. This review outlines the metabolic-dependent mechanisms that tumors engage in when faced with oxidative stress conditions that are critical for cancer progression by producing redox cofactors. In particular, we describe how the mitochondria has a key role in regulating the interplay between redox homeostasis and metabolism within tumor cells. Last, we will discuss the potential therapeutic use of agents that directly or indirectly block metabolism.

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Citations
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Journal Article•DOI•
Reactive oxygen species (ROS) as pleiotropic physiological signalling agents.

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Helmut Sies1, Dean P. Jones2•
University of Düsseldorf1, Emory University2
30 Mar 2020-Nature Reviews Molecular Cell Biology
TL;DR: This work focuses on ROS at physiological levels and their central role in redox signalling via different post-translational modifications, denoted as ‘oxidative eustress’.
Abstract: 'Reactive oxygen species' (ROS) is an umbrella term for an array of derivatives of molecular oxygen that occur as a normal attribute of aerobic life. Elevated formation of the different ROS leads to molecular damage, denoted as 'oxidative distress'. Here we focus on ROS at physiological levels and their central role in redox signalling via different post-translational modifications, denoted as 'oxidative eustress'. Two species, hydrogen peroxide (H2O2) and the superoxide anion radical (O2·-), are key redox signalling agents generated under the control of growth factors and cytokines by more than 40 enzymes, prominently including NADPH oxidases and the mitochondrial electron transport chain. At the low physiological levels in the nanomolar range, H2O2 is the major agent signalling through specific protein targets, which engage in metabolic regulation and stress responses to support cellular adaptation to a changing environment and stress. In addition, several other reactive species are involved in redox signalling, for instance nitric oxide, hydrogen sulfide and oxidized lipids. Recent methodological advances permit the assessment of molecular interactions of specific ROS molecules with specific targets in redox signalling pathways. Accordingly, major advances have occurred in understanding the role of these oxidants in physiology and disease, including the nervous, cardiovascular and immune systems, skeletal muscle and metabolic regulation as well as ageing and cancer. In the past, unspecific elimination of ROS by use of low molecular mass antioxidant compounds was not successful in counteracting disease initiation and progression in clinical trials. However, controlling specific ROS-mediated signalling pathways by selective targeting offers a perspective for a future of more refined redox medicine. This includes enzymatic defence systems such as those controlled by the stress-response transcription factors NRF2 and nuclear factor-κB, the role of trace elements such as selenium, the use of redox drugs and the modulation of environmental factors collectively known as the exposome (for example, nutrition, lifestyle and irradiation).

1,809 citations

Journal Article•DOI•
ROS signalling in the biology of cancer.

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Jennifer N. Moloney1, Thomas G. Cotter1•
University College Cork1
03 Jun 2017-Seminars in Cell & Developmental Biology
TL;DR: The generation and sources of ROS within tumour cells, the regulation of ROS by antioxidant defence systems, as well as the effect of elevated ROS production on their signalling targets in cancer are discussed.

1,100 citations

Cites background from "ROS homeostasis and metabolism: a d..."

  • ...ROS have long een associated with cancer where different types of tumour cells ave been shown to produce elevated levels of ROS compared to heir normal counterparts [3]....

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  • ...Elevated levels of ROS and O2•− in cancer may be a result of reduced free radical scavenging enzymes, increased glucose metabolism (Warburg effect), increased receptor activity in the cell, oncogenic activity, increased presence of growth factors and cytokines or due to increased intracellular oxidant production from the mitochondria, NADPH oxidases (NOX), cyclooxygenases (COX), lipooxygenases, xanthine oxidases and cytochrome P450 enzymes [3,11,21,31,32]....

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Journal Article•DOI•
ROS in cancer therapy: the bright side of the moon

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Bruno Perillo, Marzia Di Donato, Antonio Pezone, Erika Di Zazzo, Pia Giovannelli, Giovanni Galasso, Gabriella Castoria, Antimo Migliaccio 
14 Feb 2020-Experimental and Molecular Medicine
TL;DR: The review will emphasize the molecular mechanisms useful for the development of therapeutic strategies that are based on modulating ROS levels to treat cancer, and report on the growing data that highlight the role of ROS generated by different metabolic pathways as Trojan horses to eliminate cancer cells.
Abstract: Reactive oxygen species (ROS) constitute a group of highly reactive molecules that have evolved as regulators of important signaling pathways. It is now well accepted that moderate levels of ROS are required for several cellular functions, including gene expression. The production of ROS is elevated in tumor cells as a consequence of increased metabolic rate, gene mutation and relative hypoxia, and excess ROS are quenched by increased antioxidant enzymatic and nonenzymatic pathways in the same cells. Moderate increases of ROS contribute to several pathologic conditions, among which are tumor promotion and progression, as they are involved in different signaling pathways and induce DNA mutation. However, ROS are also able to trigger programmed cell death (PCD). Our review will emphasize the molecular mechanisms useful for the development of therapeutic strategies that are based on modulating ROS levels to treat cancer. Specifically, we will report on the growing data that highlight the role of ROS generated by different metabolic pathways as Trojan horses to eliminate cancer cells.

1,004 citations

Journal Article•DOI•
Superoxide dismutases: Dual roles in controlling ROS damage and regulating ROS signaling.

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Ying Wang1, Robyn Branicky1, Alycia Noë1, Siegfried Hekimi1•
McGill University1
04 Jun 2018-Journal of Cell Biology
TL;DR: Studies in model organisms and humans are discussed, which reveal the dual roles of SOD enzymes in controlling damage and regulating signaling and the need for fine local control of ROS signaling.
Abstract: Superoxide dismutases (SODs) are universal enzymes of organisms that live in the presence of oxygen. They catalyze the conversion of superoxide into oxygen and hydrogen peroxide. Superoxide anions are the intended product of dedicated signaling enzymes as well as the byproduct of several metabolic processes including mitochondrial respiration. Through their activity, SOD enzymes control the levels of a variety of reactive oxygen species (ROS) and reactive nitrogen species, thus both limiting the potential toxicity of these molecules and controlling broad aspects of cellular life that are regulated by their signaling functions. All aerobic organisms have multiple SOD proteins targeted to different cellular and subcellular locations, reflecting the slow diffusion and multiple sources of their substrate superoxide. This compartmentalization also points to the need for fine local control of ROS signaling and to the possibility for ROS to signal between compartments. In this review, we discuss studies in model organisms and humans, which reveal the dual roles of SOD enzymes in controlling damage and regulating signaling.

903 citations

Journal Article•DOI•
ROS Generation and Antioxidant Defense Systems in Normal and Malignant Cells

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Anastasiya V. Snezhkina1, Anna V. Kudryavtseva1, Olga L. Kardymon1, Maria V Savvateeva1, Nataliya V. Melnikova1, George S. Krasnov1, Alexey A. Dmitriev1 •
Engelhardt Institute of Molecular Biology1
05 Aug 2019-Oxidative Medicine and Cellular Longevity
TL;DR: This review covers the current data on the mechanisms of ROS generation and existing antioxidant systems balancing the redox state in mammalian cells that can also be related to tumors.
Abstract: Reactive oxygen species (ROS) are by-products of normal cell activity. They are produced in many cellular compartments and play a major role in signaling pathways. Overproduction of ROS is associated with the development of various human diseases (including cancer, cardiovascular, neurodegenerative, and metabolic disorders), inflammation, and aging. Tumors continuously generate ROS at increased levels that have a dual role in their development. Oxidative stress can promote tumor initiation, progression, and resistance to therapy through DNA damage, leading to the accumulation of mutations and genome instability, as well as reprogramming cell metabolism and signaling. On the contrary, elevated ROS levels can induce tumor cell death. This review covers the current data on the mechanisms of ROS generation and existing antioxidant systems balancing the redox state in mammalian cells that can also be related to tumors.

451 citations

Cites background from "ROS homeostasis and metabolism: a d..."

  • ...Changes in redox homeostasis contribute to cancer development and progression [54]....

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References
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Journal Article•DOI•
Understanding the Warburg Effect: The Metabolic Requirements of Cell Proliferation

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Matthew G. Vander Heiden1, Lewis C. Cantley1, Craig B. Thompson2•
Harvard University1, University of Pennsylvania2
22 May 2009-Science
TL;DR: It is proposed that the metabolism of cancer cells, and indeed all proliferating cells, is adapted to facilitate the uptake and incorporation of nutrients into the biomass needed to produce a new cell.
Abstract: In contrast to normal differentiated cells, which rely primarily on mitochondrial oxidative phosphorylation to generate the energy needed for cellular processes, most cancer cells instead rely on aerobic glycolysis, a phenomenon termed “the Warburg effect.” Aerobic glycolysis is an inefficient way to generate adenosine 5′-triphosphate (ATP), however, and the advantage it confers to cancer cells has been unclear. Here we propose that the metabolism of cancer cells, and indeed all proliferating cells, is adapted to facilitate the uptake and incorporation of nutrients into the biomass (e.g., nucleotides, amino acids, and lipids) needed to produce a new cell. Supporting this idea are recent studies showing that (i) several signaling pathways implicated in cell proliferation also regulate metabolic pathways that incorporate nutrients into biomass; and that (ii) certain cancer-associated mutations enable cancer cells to acquire and metabolize nutrients in a manner conducive to proliferation rather than efficient ATP production. A better understanding of the mechanistic links between cellular metabolism and growth control may ultimately lead to better treatments for human cancer.

12,380 citations

"ROS homeostasis and metabolism: a d..." refers background in this paper

  • ...Several studies indicate that the pro-glycolytic shift caused by oncogene activation and loss of tumor suppressors represents a selective advantage for tumors by providing essential precursors for building the macromolecules required to sustain growth and proliferation.(72,73) As a matter of fact, therapeutic modulation of glucose metabolism and...

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Journal Article•DOI•
ROS Function in Redox Signaling and Oxidative Stress

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Michael Schieber1, Navdeep S. Chandel1•
Northwestern University1
19 May 2014-Current Biology
TL;DR: It is argued that redox biology, rather than oxidative stress, underlies physiological and pathological conditions.

4,297 citations

"ROS homeostasis and metabolism: a d..." refers background in this paper

  • ...As a consequence of oxidative metabolism, physiological amounts of ROS are produced at the level of the mETC, inducing the pro-tumoral activation of redox-sensitive pathways.(31) To prevent ROS-induced toxicity, cancer cells redirect the metabolic intermediates coming from glutamine and one-carbon metabolism into alternative pathways that generate NADPH and GSH, antioxidants molecules readily used by several ROS-scavenging enzymes....

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Journal Article•DOI•
Regulation of cancer cell metabolism

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Rob A. Cairns, Isaac S. Harris, Tak W. Mak
01 Feb 2011-Nature Reviews Cancer
TL;DR: Interest in the topic of tumour metabolism has waxed and waned over the past century, but it has become clear that many of the signalling pathways that are affected by genetic mutations and the tumour microenvironment have a profound effect on core metabolism, making this topic once again one of the most intense areas of research in cancer biology.
Abstract: Interest in the topic of tumour metabolism has waxed and waned over the past century of cancer research. The early observations of Warburg and his contemporaries established that there are fundamental differences in the central metabolic pathways operating in malignant tissue. However, the initial hypotheses that were based on these observations proved inadequate to explain tumorigenesis, and the oncogene revolution pushed tumour metabolism to the margins of cancer research. In recent years, interest has been renewed as it has become clear that many of the signalling pathways that are affected by genetic mutations and the tumour microenvironment have a profound effect on core metabolism, making this topic once again one of the most intense areas of research in cancer biology.

4,169 citations

"ROS homeostasis and metabolism: a d..." refers background in this paper

  • ...Glucose is then converted to glucose-6-phosphate by hexokinase enzymes and enters into a series of ten enzyme-catalyzed reactions culminating in the generation of pyruvate, adenosine tris-phosphate (ATP) and reduced cofactors in the form of NADH.(71) As already observed by...

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  • ...Glucose is then converted to glucose-6-phosphate by hexokinase enzymes and enters into a series of ten enzyme-catalyzed reactions culminating in the generation of pyruvate, adenosine tris-phosphate (ATP) and reduced cofactors in the form of NADH.71 As already observed by Otto Warburg in the 1924, tumor cells exhibit a prevalent use of the glycolytic pathway regardless the presence of sufficient oxygen tension, a phenomenon known as Warburg effect.64 Several studies indicate that the pro-glycolytic shift caused by oncogene activation and loss of tumor suppressors represents a selective advantage for tumors by providing essential precursors for building the macromolecules required to sustain growth and proliferation.72,73 As a matter of fact, therapeutic modulation of glucose metabolism and transport has been widely utilized as an effective anticancer strategy.74–80 It is now understood that glucose metabolism has an essential role in the control of redox homeostasis in Cell Death and Disease tumors, as glycolytic intermediates can be shuttled into the metabolic pathways that directly or indirectly contribute to generate reducing equivalents, mainly PPP-derived NADPH or glutaminolysis-derived GSH....

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Journal Article•DOI•
Regulation of Ferroptotic Cancer Cell Death by GPX4

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Wan Seok Yang1, Rohitha SriRamaratnam1, Matthew Welsch1, Kenichi Shimada1, Rachid Skouta1, Vasanthi S. Viswanathan2, Vasanthi S. Viswanathan1, Jaime H. Cheah2, Paul A. Clemons2, Alykhan F. Shamji2, Clary B. Clish2, Lewis M. Brown1, Albert W. Girotti3, Virginia W. Cornish1, Stuart L. Schreiber2, Brent R. Stockwell •
Columbia University1, Broad Institute2, Medical College of Wisconsin3
16 Jan 2014-Cell
TL;DR: Targeted metabolomic profiling and chemoproteomics revealed that GPX4 is an essential regulator of ferroptotic cancer cell death and sensitivity profiling in 177 cancer cell lines revealed that diffuse large B cell lymphomas and renal cell carcinomas are particularly susceptible to GPx4-regulated ferroPTosis.

3,457 citations

"ROS homeostasis and metabolism: a d..." refers background in this paper

  • ...lymphomas and renal cell carcinomas with Ras mutations were found to be particularly susceptible to ferroptosis upon BSO-mediated GSH depletion, decreased Gpx4 activity and accumulation of lipid peroxidation.(168,169) In another study erastin, a potent inhibitor of Xc − cystine importer was shown to induce ER stress and trigger ferroptosis in different cancer cell lines....

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Journal Article•DOI•
Reactive oxygen species (ROS) homeostasis and redox regulation in cellular signaling

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Paul D. Ray1, Bo-Wen Huang1, Yoshiaki Tsuji1•
North Carolina State University1
01 May 2012-Cellular Signalling
TL;DR: This review focuses on the molecular mechanisms through which ROS directly interact with critical signaling molecules to initiate signaling in a broad variety of cellular processes, such as proliferation and survival, ROS homeostasis and antioxidant gene regulation, mitochondrial oxidative stress, apoptosis, and aging.

3,372 citations

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Targeting cancer cells by ROS-mediated mechanisms: a radical therapeutic approach?

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ROS Function in Redox Signaling and Oxidative Stress

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