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Cancers
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Metabolic Pathways and Redox Homeostasis in Cancer
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Metabolic Pathways and Redox Homeostasis in Cancer

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Molecular Cancer Biology".

Deadline for manuscript submissions: closed (30 November 2020) | Viewed by 64047

Special Issue Editors

Dr. Jacques Pouyssegur

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Guest Editor
1. Institute of Research on Cancer and Aging (IRCAN), University of Nice-Sophia Antipolis-CNRS-Inserm, Centre A. Lacassagne, 06189 Nice, France
2. Centre Scientifique de Monaco (CSM), 8 Quai Antoine Ier MC 98000 Monaco, Monaco
Interests: Hypoxic signaling and cancer metabolism; Acid, nutritional and oxidative stress in cancers
Special Issues, Collections and Topics in MDPI journals
Dr. Milica VUCETIC

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Guest Editor
Centre Scientifique de Monaco (CSM), 8 Quai Antoine Ier MC 98000 Monaco, Monaco
Interests: nutritional and oxidative stress in cancers
Special Issues, Collections and Topics in MDPI journals
Dr. Fatima Mechta-Grigoriou

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Guest Editor
Institut Curie, Paris, France

Special Issue Information

Dear Colleagues,

Tumour metabolism is one of the oldest field in cancer biology, dating back to the seminal work of Otto Warburg in the 1920s. Great work in the late 1995–2005 in the hypoxia field, recently awarded by Nobel Prize, paved the way in the understanding how cancer cells adopt their metabolism, survive and even thrive in the conditions of low oxygen and nutrient supply. Metabolic plasticity of cancer cells, by their diversities and opportunities, continues to impress and inspire scientists all around the world in the last two decades. Even more complex and puzzling is the question of cancer redox homeostasis, where e.g., high level of reactive oxygen species (ROS) has been recognized as both pro-oncogenic (correlating with increased incidence of cancer) and anti-oncogenic (mechanism exploited by many chemotherapeutics and new form of cell death, like ferroptosis). Thus, further comprehensive research, as well as pre-clinical approaches, are required in order to maximally exploit these vulnerability points of the Biology/Physiology of Cancer.

This special issue on “Metabolic Pathways and Redox Homeostasis in Cancer” welcomes both original and review articles.

Dr. Jacques Pouyssegur
Dr. Milica VUCETIC
Dr. Fatima Mechta-Grigoriou
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Warburg effect
  • fermentative glycolysis
  • lactic acid
  • hypoxia
  • oxphos
  • cysteine homeostasis
  • transsulfuration pathway
  • cystine transport
  • glutathione
  • tumour microenvironment
  • cancer-associated fibroblasts
  • immune cells

Published Papers (10 papers)

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Research

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20 pages, 2827 KiB  
Article
A Cystine-Cysteine Intercellular Shuttle Prevents Ferroptosis in xCTKO Pancreatic Ductal Adenocarcinoma Cells
by Willian Meira, Boutaina Daher, Scott Kenneth Parks, Yann Cormerais, Jerome Durivault, Eric Tambutte, Jacques Pouyssegur and Milica Vučetić
Cancers 2021, 13(6), 1434; https://doi.org/10.3390/cancers13061434 - 21 Mar 2021
Cited by 17 | Viewed by 4180
Abstract
In our previous study, we showed that a cystine transporter (xCT) plays a pivotal role in ferroptosis of pancreatic ductal adenocarcinoma (PDAC) cells in vitro. However, in vivo xCTKO cells grew normally indicating that a mechanism exists to drastically suppress the ferroptotic [...] Read more.
In our previous study, we showed that a cystine transporter (xCT) plays a pivotal role in ferroptosis of pancreatic ductal adenocarcinoma (PDAC) cells in vitro. However, in vivo xCTKO cells grew normally indicating that a mechanism exists to drastically suppress the ferroptotic phenotype. We hypothesized that plasma and neighboring cells within the tumor mass provide a source of cysteine to confer full ferroptosis resistance to xCTKO PDAC cells. To evaluate this hypothesis, we (co-) cultured xCTKO PDAC cells with different xCT-proficient cells or with their conditioned media. Our data unequivocally showed that the presence of a cysteine/cystine shuttle between neighboring cells is the mechanism that provides redox and nutrient balance, and thus ferroptotic resistance in xCTKO cells. Interestingly, although a glutathione shuttle between cells represents a good alternative hypothesis as a “rescue-mechanism”, our data clearly demonstrated that the xCTKO phenotype is suppressed even with conditioned media from cells lacking the glutathione biosynthesis enzyme. Furthermore, we demonstrated that prevention of lipid hydroperoxide accumulation in vivo is mediated by import of cysteine into xCTKO cells via several genetically and pharmacologically identified transporters (ASCT1, ASCT2, LAT1, SNATs). Collectively, these data highlight the importance of the tumor environment in the ferroptosis sensitivity of cancer cells. Full article
(This article belongs to the Special Issue Metabolic Pathways and Redox Homeostasis in Cancer)
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22 pages, 3860 KiB  
Article
Cysteine and Folate Metabolism Are Targetable Vulnerabilities of Metastatic Colorectal Cancer
by Josep Tarragó-Celada, Carles Foguet, Míriam Tarrado-Castellarnau, Silvia Marin, Xavier Hernández-Alias, Jordi Perarnau, Fionnuala Morrish, David Hockenbery, Roger R. Gomis, Eytan Ruppin, Mariia Yuneva, Pedro de Atauri and Marta Cascante
Cancers 2021, 13(3), 425; https://doi.org/10.3390/cancers13030425 - 23 Jan 2021
Cited by 11 | Viewed by 4186
Abstract
With most cancer-related deaths resulting from metastasis, the development of new therapeutic approaches against metastatic colorectal cancer (mCRC) is essential to increasing patient survival. The metabolic adaptations that support mCRC remain undefined and their elucidation is crucial to identify potential therapeutic targets. Here, [...] Read more.
With most cancer-related deaths resulting from metastasis, the development of new therapeutic approaches against metastatic colorectal cancer (mCRC) is essential to increasing patient survival. The metabolic adaptations that support mCRC remain undefined and their elucidation is crucial to identify potential therapeutic targets. Here, we employed a strategy for the rational identification of targetable metabolic vulnerabilities. This strategy involved first a thorough metabolic characterisation of same-patient-derived cell lines from primary colon adenocarcinoma (SW480), its lymph node metastasis (SW620) and a liver metastatic derivative (SW620-LiM2), and second, using a novel multi-omics integration workflow, identification of metabolic vulnerabilities specific to the metastatic cell lines. We discovered that the metastatic cell lines are selectively vulnerable to the inhibition of cystine import and folate metabolism, two key pathways in redox homeostasis. Specifically, we identified the system xCT and MTHFD1 genes as potential therapeutic targets, both individually and combined, for combating mCRC. Full article
(This article belongs to the Special Issue Metabolic Pathways and Redox Homeostasis in Cancer)
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16 pages, 4716 KiB  
Article
Pharmacotranscriptomic Analysis Reveals Novel Drugs and Gene Networks Regulating Ferroptosis in Cancer
by Haitang Yang, Liang Zhao, Yanyun Gao, Feng Yao, Thomas M. Marti, Ralph A. Schmid and Ren-Wang Peng
Cancers 2020, 12(11), 3273; https://doi.org/10.3390/cancers12113273 - 05 Nov 2020
Cited by 24 | Viewed by 3876
Abstract
(1) Background: Ferroptosis is an apoptosis-independent cell death program implicated in many diseases including cancer. Emerging evidence suggests ferroptosis as a promising avenue for cancer therapy, but the paucity of mechanistic understanding of ferroptosis regulation and lack of biomarkers for sensitivity to ferroptosis [...] Read more.
(1) Background: Ferroptosis is an apoptosis-independent cell death program implicated in many diseases including cancer. Emerging evidence suggests ferroptosis as a promising avenue for cancer therapy, but the paucity of mechanistic understanding of ferroptosis regulation and lack of biomarkers for sensitivity to ferroptosis inducers have significantly hampered the utility of ferroptosis-based therapy. (2) Methods: We performed integrated dataset analysis by correlating the sensitivity of small-molecule compounds (n = 481) against the transcriptomes of solid cancer cell lines (n = 659) to identify drug candidates with the potential to induce ferroptosis. Generalizable gene signatures of ferroptosis sensitivity and resistance are defined by interrogating drug effects of ferroptosis inducers (n = 7) with transcriptomic data of pan-solid cancer cells. (3) Results: We report, for the first time, the comprehensive identification of drug compounds that induce ferroptosis and the delineation of generalizable gene signatures of pro- and anti-ferroptosis in pan-cancer. We further reveal that small cell lung cancer (SCLC) and isocitrate dehydrogenase (IDH1/2)-mutant brain tumors show enrichment of pro-ferroptosis gene signature, suggesting a unique vulnerability of SCLC and IDH-mutant tumors to ferroptosis inducers. Finally, we demonstrate that targeting class I histone deacetylase (HDAC) significantly enhances ferroptotic cell death caused by Erastin, an ferroptosis inducer, in lung cancer cells, revealing a previously underappreciated role for HDAC in ferroptosis regulation. (4) Conclusions: Our work reveals novel drug compounds and gene networks that regulate ferroptosis in cancer, which sheds light on the mechanisms of ferroptosis and may facilitate biomarker-guided stratification for ferroptosis-based therapy. Full article
(This article belongs to the Special Issue Metabolic Pathways and Redox Homeostasis in Cancer)
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Review

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14 pages, 1054 KiB  
Review
NUPR1: A Critical Regulator of the Antioxidant System
by Can Huang, Patricia Santofimia-Castaño and Juan Iovanna
Cancers 2021, 13(15), 3670; https://doi.org/10.3390/cancers13153670 - 22 Jul 2021
Cited by 22 | Viewed by 5213
Abstract
Nuclear protein 1 (NUPR1) is a small intrinsically disordered protein (IDP) activated in response to various types of cellular stress, including endoplasmic reticulum (ER) stress and oxidative stress. Reactive oxygen species (ROS) are mainly produced during mitochondrial oxidative metabolism, and directly impact redox [...] Read more.
Nuclear protein 1 (NUPR1) is a small intrinsically disordered protein (IDP) activated in response to various types of cellular stress, including endoplasmic reticulum (ER) stress and oxidative stress. Reactive oxygen species (ROS) are mainly produced during mitochondrial oxidative metabolism, and directly impact redox homeostasis and oxidative stress. Ferroptosis is a ROS-dependent programmed cell death driven by an iron-mediated redox reaction. Substantial evidence supports a maintenance role of the stress-inducible protein NUPR1 on cancer cell metabolism that confers chemotherapeutic resistance by upregulating mitochondrial function-associated genes and various antioxidant genes in cancer cells. NUPR1, identified as an antagonist of ferroptosis, plays an important role in redox reactions. This review summarizes the current knowledge on the mechanism behind the observed impact of NUPR1 on mitochondrial function, energy metabolism, iron metabolism, and the antioxidant system. The therapeutic potential of genetic or pharmacological inhibition of NUPR1 in cancer is also discussed. Understanding the role of NUPR1 in the antioxidant system and the mechanisms behind its regulation of ferroptosis may promote the development of more efficacious strategies for cancer therapy. Full article
(This article belongs to the Special Issue Metabolic Pathways and Redox Homeostasis in Cancer)
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23 pages, 1390 KiB  
Review
Tumor Cells and Cancer-Associated Fibroblasts: An Updated Metabolic Perspective
by Géraldine Gentric and Fatima Mechta-Grigoriou
Cancers 2021, 13(3), 399; https://doi.org/10.3390/cancers13030399 - 22 Jan 2021
Cited by 26 | Viewed by 3900
Abstract
During the past decades, metabolism and redox imbalance have gained considerable attention in the cancer field. In addition to the well-known Warburg effect occurring in tumor cells, numerous other metabolic deregulations have now been reported. Indeed, metabolic reprograming in cancer is much more [...] Read more.
During the past decades, metabolism and redox imbalance have gained considerable attention in the cancer field. In addition to the well-known Warburg effect occurring in tumor cells, numerous other metabolic deregulations have now been reported. Indeed, metabolic reprograming in cancer is much more heterogeneous than initially thought. In particular, a high diversity of carbon sources used by tumor cells has now been shown to contribute to this metabolic heterogeneity in cancer. Moreover, the molecular mechanisms newly highlighted are multiple and shed light on novel actors. Furthermore, the impact of this metabolic heterogeneity on tumor microenvironment has also been an intense subject of research recently. Here, we will describe the new metabolic pathways newly uncovered in tumor cells. We will also have a particular focus on Cancer-Associated Fibroblasts (CAF), whose identity, function and metabolism have been recently under profound investigation. In that sense, we will discuss about the metabolic crosstalk between tumor cells and CAF. Full article
(This article belongs to the Special Issue Metabolic Pathways and Redox Homeostasis in Cancer)
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17 pages, 2871 KiB  
Review
The p53 Pathway and Metabolism: The Tree That Hides the Forest
by Airelle Lahalle, Matthieu Lacroix, Carlo De Blasio, Madi Y. Cissé, Laetitia K. Linares and Laurent Le Cam
Cancers 2021, 13(1), 133; https://doi.org/10.3390/cancers13010133 - 04 Jan 2021
Cited by 29 | Viewed by 4844
Abstract
The p53 pathway is functionally inactivated in most, if not all, human cancers. The p53 protein is a central effector of numerous stress-related molecular cascades. p53 controls a safeguard mechanism that prevents accumulation of abnormal cells and their transformation by regulating DNA repair, [...] Read more.
The p53 pathway is functionally inactivated in most, if not all, human cancers. The p53 protein is a central effector of numerous stress-related molecular cascades. p53 controls a safeguard mechanism that prevents accumulation of abnormal cells and their transformation by regulating DNA repair, cell cycle progression, cell death, or senescence. The multiple cellular processes regulated by p53 were more recently extended to the control of metabolism and many studies support the notion that perturbations of p53-associated metabolic activities are linked to cancer development, as well as to other pathophysiological conditions including aging, type II diabetes, and liver disease. Although much less documented than p53 metabolic activities, converging lines of evidence indicate that other key components of this tumor suppressor pathway are also involved in cellular metabolism through p53-dependent as well as p53-independent mechanisms. Thus, at least from a metabolic standpoint, the p53 pathway must be considered as a non-linear pathway, but the complex metabolic network controlled by these p53 regulators and the mechanisms by which their activities are coordinated with p53 metabolic functions remain poorly understood. In this review, we highlight some of the metabolic pathways controlled by several central components of the p53 pathway and their role in tissue homeostasis, metabolic diseases, and cancer. Full article
(This article belongs to the Special Issue Metabolic Pathways and Redox Homeostasis in Cancer)
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33 pages, 1863 KiB  
Review
Amino Acid Transporters on the Guard of Cell Genome and Epigenome
by Uğur Kahya, Ayşe Sedef Köseer and Anna Dubrovska
Cancers 2021, 13(1), 125; https://doi.org/10.3390/cancers13010125 - 02 Jan 2021
Cited by 19 | Viewed by 7437
Abstract
Tumorigenesis is driven by metabolic reprogramming. Oncogenic mutations and epigenetic alterations that cause metabolic rewiring may also upregulate the reactive oxygen species (ROS). Precise regulation of the intracellular ROS levels is critical for tumor cell growth and survival. High ROS production leads to [...] Read more.
Tumorigenesis is driven by metabolic reprogramming. Oncogenic mutations and epigenetic alterations that cause metabolic rewiring may also upregulate the reactive oxygen species (ROS). Precise regulation of the intracellular ROS levels is critical for tumor cell growth and survival. High ROS production leads to the damage of vital macromolecules, such as DNA, proteins, and lipids, causing genomic instability and further tumor evolution. One of the hallmarks of cancer metabolism is deregulated amino acid uptake. In fast-growing tumors, amino acids are not only the source of energy and building intermediates but also critical regulators of redox homeostasis. Amino acid uptake regulates the intracellular glutathione (GSH) levels, endoplasmic reticulum stress, unfolded protein response signaling, mTOR-mediated antioxidant defense, and epigenetic adaptations of tumor cells to oxidative stress. This review summarizes the role of amino acid transporters as the defender of tumor antioxidant system and genome integrity and discusses them as promising therapeutic targets and tumor imaging tools. Full article
(This article belongs to the Special Issue Metabolic Pathways and Redox Homeostasis in Cancer)
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22 pages, 1911 KiB  
Review
The Metabolic Heterogeneity and Flexibility of Cancer Stem Cells
by Atsushi Tanabe and Hiroeki Sahara
Cancers 2020, 12(10), 2780; https://doi.org/10.3390/cancers12102780 - 28 Sep 2020
Cited by 29 | Viewed by 3945
Abstract
Numerous findings have indicated that CSCs, which are present at a low frequency inside primary tumors, are the main cause of therapy resistance and cancer recurrence. Although various therapeutic methods targeting CSCs have been attempted for eliminating cancer cells completely, the complicated characteristics [...] Read more.
Numerous findings have indicated that CSCs, which are present at a low frequency inside primary tumors, are the main cause of therapy resistance and cancer recurrence. Although various therapeutic methods targeting CSCs have been attempted for eliminating cancer cells completely, the complicated characteristics of CSCs have hampered such attempts. In analyzing the biological properties of CSCs, it was revealed that CSCs have a peculiar metabolism that is distinct from non-CSCs to maintain their stemness properties. The CSC metabolism involves not only the catabolic and anabolic pathways, but also intracellular signaling, gene expression, and redox balance. In addition, CSCs can reprogram their metabolism to flexibly respond to environmental changes. In this review, we focus on the flexible metabolic mechanisms of CSCs, and highlight the new therapeutics that target CSC metabolism. Full article
(This article belongs to the Special Issue Metabolic Pathways and Redox Homeostasis in Cancer)
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22 pages, 1045 KiB  
Review
Warburg and Beyond: The Power of Mitochondrial Metabolism to Collaborate or Replace Fermentative Glycolysis in Cancer
by Shamir Cassim, Milica Vučetić, Maša Ždralević and Jacques Pouyssegur
Cancers 2020, 12(5), 1119; https://doi.org/10.3390/cancers12051119 - 30 Apr 2020
Cited by 110 | Viewed by 9944
Abstract
A defining hallmark of tumor phenotypes is uncontrolled cell proliferation, while fermentative glycolysis has long been considered as one of the major metabolic pathways that allows energy production and provides intermediates for the anabolic growth of cancer cells. Although such a vision has [...] Read more.
A defining hallmark of tumor phenotypes is uncontrolled cell proliferation, while fermentative glycolysis has long been considered as one of the major metabolic pathways that allows energy production and provides intermediates for the anabolic growth of cancer cells. Although such a vision has been crucial for the development of clinical imaging modalities, it has become now evident that in contrast to prior beliefs, mitochondria play a key role in tumorigenesis. Recent findings demonstrated that a full genetic disruption of the Warburg effect of aggressive cancers does not suppress but instead reduces tumor growth. Tumor growth then relies exclusively on functional mitochondria. Besides having fundamental bioenergetic functions, mitochondrial metabolism indeed provides appropriate building blocks for tumor anabolism, controls redox balance, and coordinates cell death. Hence, mitochondria represent promising targets for the development of novel anti-cancer agents. Here, after revisiting the long-standing Warburg effect from a historic and dynamic perspective, we review the role of mitochondria in cancer with particular attention to the cancer cell-intrinsic/extrinsic mechanisms through which mitochondria influence all steps of tumorigenesis, and briefly discuss the therapeutic potential of targeting mitochondrial metabolism for cancer therapy. Full article
(This article belongs to the Special Issue Metabolic Pathways and Redox Homeostasis in Cancer)
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31 pages, 2085 KiB  
Review
Metabolic Heterogeneity of Cancer Cells: An Interplay between HIF-1, GLUTs, and AMPK
by Nurbubu T. Moldogazieva, Innokenty M. Mokhosoev and Alexander A. Terentiev
Cancers 2020, 12(4), 862; https://doi.org/10.3390/cancers12040862 - 02 Apr 2020
Cited by 94 | Viewed by 15481
Abstract
It has been long recognized that cancer cells reprogram their metabolism under hypoxia conditions due to a shift from oxidative phosphorylation (OXPHOS) to glycolysis in order to meet elevated requirements in energy and nutrients for proliferation, migration, and survival. However, data accumulated over [...] Read more.
It has been long recognized that cancer cells reprogram their metabolism under hypoxia conditions due to a shift from oxidative phosphorylation (OXPHOS) to glycolysis in order to meet elevated requirements in energy and nutrients for proliferation, migration, and survival. However, data accumulated over recent years has increasingly provided evidence that cancer cells can revert from glycolysis to OXPHOS and maintain both reprogrammed and oxidative metabolism, even in the same tumor. This phenomenon, denoted as cancer cell metabolic plasticity or hybrid metabolism, depends on a tumor micro-environment that is highly heterogeneous and influenced by an intensity of vasculature and blood flow, oxygen concentration, and nutrient and energy supply, and requires regulatory interplay between multiple oncogenes, transcription factors, growth factors, and reactive oxygen species (ROS), among others. Hypoxia-inducible factor-1 (HIF-1) and AMP-activated protein kinase (AMPK) represent key modulators of a switch between reprogrammed and oxidative metabolism. The present review focuses on cross-talks between HIF-1, glucose transporters (GLUTs), and AMPK with other regulatory proteins including oncogenes such as c-Myc, p53, and KRAS; growth factor-initiated protein kinase B (PKB)/Akt, phosphatidyl-3-kinase (PI3K), and mTOR signaling pathways; and tumor suppressors such as liver kinase B1 (LKB1) and TSC1 in controlling cancer cell metabolism. The multiple switches between metabolic pathways can underlie chemo-resistance to conventional anti-cancer therapy and should be taken into account in choosing molecular targets to discover novel anti-cancer drugs. Full article
(This article belongs to the Special Issue Metabolic Pathways and Redox Homeostasis in Cancer)
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