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Regulation of the Cellular Redox Environment by Superoxide Dismutases, Catalase, and Glutathione Peroxidases During Tumor Metastasis

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Redox-Active Therapeutics

Abstract

The lethality of most cancers can be attributed to metastatic progression. Metastatic tumor cells adapt and cope with various stressful environments to enable survival during their metastatic journey which starts with the escape from the primary tumor and ends in colonization of secondary sites. Stressors of metastatic tumor microenvironments include deprivation of oxygen (hypoxia), inflammation, and chemo- and radiotherapeutic exposure, which have the propensity to expose cells to reactive oxygen species (ROS). Further, many tumor-associated cells, including cancer-associated fibroblasts, macrophages, and senescent cells within the tumor microenvironment, contribute to this ROS production. In addition to these exogenous sources, tumor cells themselves produce and are able to cope with elevated intracellular ROS. Increased ROS production outside and within metastatic tumor cells has been associated with a number of pro-metastatic events including angiogenesis, invasion, migration, survival, and anchorage-independent cell survival (anoikis resistance). Large surges of ROS can lead to oxidation of macromolecules and largely irreversible damage that may cause mitochondrial damage, leading to alterations in cancer metabolism, and genomic instability and carcinogenesis. More subtle changes in ROS lead to redox-signaling, primarily by reversible oxidation of thiols, which has been shown to contribute to pro-metastatic behavior. To cope with these changes in both intracellular and extracellular redox environments, tumor cells have uniquely evolved to alter their antioxidant enzyme expression. The present review focuses on antioxidant enzymes important in the regulation of H2O2 balance within metastatic tumor cells. It aims to highlight some of the dichotomous roles demonstrated for these enzymes in cancer etiology, and how their enzymatic activity may further influence the tumor redox environment and consequently regulate carcinogenesis and metastasis. We focus on the role of superoxide dismutases, catalase, and glutathione peroxidases and give examples on their demonstrated roles as both tumor suppressors and promoters. Specifically, we discuss how metastatic cancer cells uniquely adapt to alter expression of these enzymes and how this may contribute to changes in the intracellular redox environment to drive certain metastatic phenotypes. To therapeutically target these ROS-mediated pathways in metastatic disease will require further insights into the specificity of the ROS involved and their spatiotemporal regulation in the context of the antioxidant enzymes present.

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Abbreviations

AhR:

Aryl hydrocarbon receptor

AML:

Acute myelogenous leukemia

AMPK:

AMP activated-kinase A

Cat:

Catalase

CRPC:

Castration-resistant prostate cancer

CuZnSod/Sod1:

Cytosolic/Copper-Zinc superoxide dismutase

EcSod/Sod3:

Extracellular superoxide dismutase

EMT:

Epithelial to mesenchymal transition

fALS:

Familial amyotrophic lateral sclerosis

FAK:

Focal adhesion kinase

Foxo:

Forkhead box O

GAC:

Gastric adenocarcinoma

GPx:

Glutathione peroxidases

GR:

Glutathione reductase

GSH:

Glutathione

HCC:

Hepatocellular carcinoma

H2O2 :

Hydrogen peroxide

iNOS:

Inducible nitric oxide synthase

IL-6:

Interleukin-6

Keap1:

Kelch-like erythroid cell-derived protein with CNC homology (ECH)-associated protein 1

MAPK:

Mitogen-activated protein kinase

MMP-1:

Matrix metalloproteinase 1

MnSod/Sod2:

Mitochondrial/Manganese superoxide dismutase

mTOR:

Mechanistic target of rapamycin

NADPH:

Nicotinamide adenine dinucleotide phosphate

NF-κB:

Nuclear factor κ B

Nox:

NADPH oxidase

Nrf2:

Nuclear factor erythroid 2 (NF-E2)-related factor 2

O2 :

Oxygen

O2 •− :

Superoxide

OH• :

Hydroxyl radical

ONOO− :

Peroxynitrite

PI3K:

Phosphoinositide 3-kinase

PKB:

Protein kinase B (also known as Akt)

PHD:

Prolyl hydroxylase

PPAR α:

Peroxisome proliferator activated receptor α

PTP:

Protein tyrosine phosphatases

SBP1:

Selenium-binding protein 1

SNPs:

Single nucleotide polymorphisms

Sod:

Superoxide dismutase

RNS:

Reactive nitrogen species

ROS:

Reactive oxygen species

TM:

Tetrathiomolybdate

TNF-α:

Tumor necrosis factor α

TRX:

Thioredoxin

UCP:

Mitochondrial uncoupling proteins

WT1:

Wilm’s tumor suppressor 1

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    Authors and Affiliations

    1. Nanobioscience Constellation, Colleges of Nanoscale Science and Engineering, SUNY Polytechnic Institute, State University of New York, Albany, NY, USA

      L. P. Madhubhani P. Hemachandra, Akshaya Chandrasekaran & J. Andres Melendez

    2. Department of Pharmacology, Penn State College of Medicine, 500 University Drive, 850, Hershey, PA, 17033-0850, USA

      Nadine Hempel Ph.D.

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    1. L. P. Madhubhani P. Hemachandra
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    2. Akshaya Chandrasekaran
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    3. J. Andres Melendez
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    4. Nadine Hempel Ph.D.
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    Correspondence to Nadine Hempel Ph.D. .

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    1. Duke University School of Medicine, Durham, North Carolina, USA

      Ines Batinić-Haberle

    2. Universidade Federal da Paraíba, João Pessoa, Paraíba, Brazil

      Júlio S. Rebouças

    3. Duke University School of Medicine, Durham, North Carolina, USA

      Ivan Spasojević

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    Hemachandra, L.P.M.P., Chandrasekaran, A., Melendez, J.A., Hempel, N. (2016). Regulation of the Cellular Redox Environment by Superoxide Dismutases, Catalase, and Glutathione Peroxidases During Tumor Metastasis. In: Batinić-Haberle, I., Rebouças, J., Spasojević, I. (eds) Redox-Active Therapeutics. Oxidative Stress in Applied Basic Research and Clinical Practice. Springer, Cham. https://doi.org/10.1007/978-3-319-30705-3_4

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