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The multifaceted role of reactive oxygen species in tumorigenesis

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Abstract

Redox homeostasis is an essential requirement of the biological systems for performing various normal cellular functions including cellular growth, differentiation, senescence, survival and aging in humans. The changes in the basal levels of reactive oxygen species (ROS) are detrimental to cells and often lead to several disease conditions including cardiovascular, neurological, diabetes and cancer. During the last two decades, substantial research has been done which clearly suggests that ROS are essential for the initiation, progression, angiogenesis as well as metastasis of cancer in several ways. During the last two decades, the potential of dysregulated ROS to enhance tumor formation through the activation of various oncogenic signaling pathways, DNA mutations, immune escape, tumor microenvironment, metastasis, angiogenesis and extension of telomere has been discovered. At present, surgery followed by chemotherapy and/or radiotherapy is the major therapeutic modality for treating patients with either early or advanced stages of cancer. However, the majority of patients relapse or did not respond to initial treatment. One of the reasons for recurrence/relapse is the altered levels of ROS in tumor cells as well as in cancer-initiating stem cells. One of the critical issues is targeting the intracellular/extracellular ROS for significant antitumor response and relapse-free survival. Indeed, a large number of FDA-approved anticancer drugs are efficient to eliminate cancer cells and drug resistance by increasing ROS production. Thus, the modulation of oxidative stress response might represent a potential approach to eradicate cancer in combination with FDA-approved chemotherapies, radiotherapies as well as immunotherapies.

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Abbreviations

5-FU:

5-Fluorouracil

ABC:

ATP-binding cassette

AML:

Adult acute myeloid leukemia

AMPK 5′:

AMP-activated protein kinase

APAF1:

Apoptosis protease-activating factor 1

ATP:

Adenosine triphosphate

ART:

Artesunate

ASK-1:

Apoptosis signal-regulated kinase 1

BSO:

Buthionine sulfoximine

BCL-2:

B cell lymphoma 2

CAR:

Chimeric antigen receptor

CAT:

Catalase

CSCs:

Cancer stem cells

EGFR:

Epidermal growth factor receptor

EGF:

Epidermal growth factor

ER:

Endoplasmic reticulum

ERK:

Extracellular regulated kinase

ETC:

Electron transport chain

EMT:

Epithelial–mesenchymal transition

eNOS:

Endothelial nitric oxide synthase

GPX:

Glutathione peroxidase

GSH:

Glutathione

GCL:

Glutamate-cysteine ligase

GSS:

GSH synthetase

GSSG:

GSH disulfide

GPX4:

Glutathione peroxidase 4

H2O2 :

Hydrogen peroxide

HCC:

Hepatocellular carcinoma

HER2:

Human epidermal growth factor receptor 2

HGF:

Hepatocyte growth factor

HIF-1:

Hypoxia-inducible factor

hTERT:

Human telomerase reverse transcriptase

IDH1:

Isocitrate dehydrogenase 1

IDH2:

Isocitrate dehydrogenase 2

IL-6:

Interleukin 6

JNK:

C-Jun N-terminal kinase

LDH:

Lactate dehydrogenase

LSC:

Leukemic stem cells

MAPK:

Mitogen-activated protein kinase

MDSC:

Myeloid-derived suppressor cell

mROS:

Mitochondrial reactive oxygen species

mtDNA:

Mitochondrial DNA

NADH:

Nicotinamide adenine dinucleotide

NF-κB:

Nuclear factor kappa-light-chain-enhancer of activated B cells

NO:

Nitrogen oxide

NOS:

Nitric oxide synthase

NOX:

NADPH oxidase

NRF2:

Nuclear factor erythroid 2-related factor 2

O2•:

Superoxide

OH•:

Hydroxy radical

OXPHOS:

Oxidative phosphorylation

PRX:

Peroxiredoxins

PDAC:

Pancreatic ductal adenocarcinoma

PD-1:

Programmed death protein 1

PD-L1:

Programmed death ligand 1

PD-L2:

Programmed death ligand 2

PDGFR:

Platelet-derived growth factor receptors

PDGF:

Platelet-derived growth factor receptors

PI3K:

Phosphoinositide 3-kinases

PML:

Promyelocytic leukemia

PTEN:

Phosphatase and tensin homolog

RTK:

Receptor tyrosine kinase

RNS:

Reactive nitrogen species

ROS:

Reactive oxygen species

SAL:

Salvicine

SOD:

Superoxide dismutase

SSZ:

Sulfasalazine

STAT3:

Signal transducer and activator of transcription 3

TF:

Transcription factor

Treg:

Regulatory T cells

TAM:

Tumor-associated macrophages

TFAM:

Mitochondrial transcription factor A

TMZ:

Temozolomide

TNBC:

Triple-negative breast cancer

UCP-2:

Uncoupling protein 2

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Acknowledgements

This work was supported and funded by the Department of Biotechnology (DBT), Government of India under its Ramalingaswami Fellowship (No. BT/RLF/Re-entry/24/2014) award to Dr. Manoj Garg and Early Career Research Award (ECRA) from Science & Engineering Research Board (SERB; ECR/2016/001519), Department of Science and Technology, Government of India. We acknowledge BioRender online software for illustration of figures.

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  1. Amity Institute of Molecular Medicine and Stem Cell Research (AIMMSCR), Amity University Campus, Sector-125, Noida, Uttar Pradesh, 201313, India

    Anuradha Kirtonia & Manoj Garg

  2. Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore

    Gautam Sethi

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MG conceived the idea and designed the format of the manuscript. MG, AK, and GS wrote the manuscript and presented the concepts in the manuscript. MG and AK created the figures and the tables. MG, AK, and GS revised the manuscript and agreed to the published version of the manuscript.

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Correspondence to Gautam Sethi or Manoj Garg.

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Kirtonia, A., Sethi, G. & Garg, M. The multifaceted role of reactive oxygen species in tumorigenesis. Cell. Mol. Life Sci. 77, 4459–4483 (2020). https://doi.org/10.1007/s00018-020-03536-5

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