ROS and oncogenesis with special reference to EMT and stemness

doi:10.1016/j.ejcb.2020.151073

European Journal of Cell Biology

Volume 99, Issues 2–3, April 2020, 151073

https://doi.org/10.1016/j.ejcb.2020.151073 Get rights and content

Abstract

Elevation of the level of intracellular reactive oxygen species (ROS) has immense implication in the biological system. On the one hand, ROS promote the signaling cascades for the maintenance of normal physiological functions, the phenomenon referred to as redox biology, and on the other hand increased ROS can cause damages to the cellular macromolecules as well as genetic material, the process known as oxidative stress. Oxidative stress acts as an etiological factor for wide varieties of pathologies, cancer being one of them. ROS is regarded as a “double-edged sword” with respect to oncogenesis. It can suppress as well as promote the malignant progression depending on the type of signaling pathway it uses. Moreover, the attribution of ROS in promoting phenotypic plasticity as well as acquisition of stemness during neoplasia has become a wide area of research. The current review discussed all the aspects of ROS in the perspective of tumor biology with special reference to epithelial-mesenchymal transition (EMT) and cancer stem cells.

Graphical abstract

Section snippets

Reactive oxygen species (ROS) and its varieties

Reactive oxygen species (ROS) are the radicals having single unpaired electron in the outermost electron shell which makes them highly reactive in nature. ROS can exist in two forms- either as free oxygen viz. superoxide, nitric oxide, hydroxyl radical, sulphoxyl radicals etc. or as non-radical species viz. oxygen singlet, ozone, hydrogen peroxide, highly reactive derivatives of lipid or carbohydrate etc. (Liou and Storz, 2010). Superoxide, hydrogen peroxide, nitric oxide and hydroxyl radicals

Cellular origin of ROS and its biological fate

Primary source of intracellular superoxide constitutes of the NADPH oxidase (NOXs) mediated oxidation of NADPH (Bedard and Krause, 2007). Mitochondrial electron leakage during aerobic respiration can also account for the superoxide generation (Jastroch et al., 2010). Within the cell superoxide gets converted into hydrogen peroxide in presence of superoxide dismutase. Generated hydrogen peroxide can oxidize the cystein residues of certain proteins to initiate redox signaling cascade. In other

Redox signaling and redox modulation

Transduction of cellular signaling involves the binding of extracellular stimulus (“first messenger”) with the receptor protein of the cell and the activated receptor can in turn activate other signaling molecules (“second messengers”). Finally, the signal is distributed to the appropriate targets through the activation of one or more signaling molecules resulting in the altered behavior of the cell. Low level of ROS produced by the process such as mitochondrial respiration or by the action of

Physiological and pathophysiological consequences of ROS

ROS has vital physiological attribution in biological system. Phagocytic cells depend on the production of intracellular ROS for the destruction of engulfed pathogen, an important aspect of innate immunity (Paiva and Bozza, 2014). As mentioned in the previous section, ROS can induce physiological response by acting as second messenger during redox signaling. Anti-oxidant can interfere with the physiological role of ROS to cause undesired consequences. It has been reported that the

CSCs

CSC hypothesis throw light on a quiescent sub-population of the bulk tumor cells that can withstand chemo and radiation therapies and accounts for the recurrence of the tumor (Zheng et al., 2013Kim et al., 2009aPhi et al., 2018) [Fig. 3]. Many studies identified CSCs as the main cause of cancer relapse (Peitzsch et al., 2017Ayob and Ramasamy, 2018Li et al., 2018). These cells possesses the stem cell properties viz. self-renewal, differentiation and are also tumorogenic when transplanted into an

Future directions

ROS has emerged as a critical factor in oncogenesis. Depending on the signaling cascade triggered, ROS can act as either tumor suppressor or tumor promoter. Moreover, ROS has the potency to promote EMT especially in hypoxic environment which may lead to the development of quiescent, drug/ chemo resistant CSC population that acts as the “cancer seed”. Thereafter the sharp paradoxical phenomenon of decline of ROS level happens in CSC to maintain the stemness property. The detailed mechanism for

Declaration of Competing Interest

Authors declare no potential conflict of interest.

Acknowledgements

Financial support from the DBT-RA Program in Biotechnology and Life Sciences is gratefully acknowledged. The work was supported by the grant from the Department of Science and Technology, Government of West Bengal, India (151(sanc.)/ST/P/S&T/ 9G-32/2016; Dated. 8.2.2018).

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ROS and oncogenesis with special reference to EMT and stemness

Abstract

Graphical abstract

Section snippets

Reactive oxygen species (ROS) and its varieties

Cellular origin of ROS and its biological fate

Redox signaling and redox modulation

Physiological and pathophysiological consequences of ROS

CSCs

Future directions

Declaration of Competing Interest

Acknowledgements

Curr. Biol.

Free Radic. Biol. Med.

Biochem. Pharmacol.

Trends Biochem. Sci.

Trends Biochem. Sci.

Toxicology

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Free Radic. Biol. Med.

Mutat. Res. Toxicol.

Biochim Biophys Acta.

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Biochimica et Biophysica Acta (BBA)-Reviews on Cancer

Reactive oxygen species in cancer

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The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology

Physiol. Rev.

Mitochondrial proton and electron leaks

Essays Biochem.

Defining ROS in biology and medicine

React. Oxyg. Species Apex (Apex)

Are reactive oxygen species always detrimental to pathogens?

Antioxid. Redox Signal.

Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis

Nature

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

Nat. Rev. Drug Discov.

Reactive oxygen species: a double-edged sword in oncogenesis

World J. Gastroenterol.

The role of p38 MAPK and JNK in Arsenic trioxide‐induced mitochondrial cell death in human cervical cancer cells

J. Cell. Physiol.

Effects of scutellarin on apoptosis induced by cobalt chloride in PC12 cells

Chin. J. Physiol.

Angiotensin II and tumor necrosis factor-α synergistically promote monocyte chemoattractant protein-1 expression: roles of NF-κB, p38, and reactive oxygen species

Am. J. Physiol. Heart and Circ. Phys.

Melatonin represses oxidative stress‐induced activation of the MAP kinase and mTOR signaling pathways in H4IIE hepatoma cells through inhibition of Ras

J. Pineal Res.

Regulation of cellular response to oncogenic and oxidative stress by seladin-1

Nature

p38α MAPK is required for contact inhibition. Regulation of malignant cell transformation by the stress-activated kinase p38α

Oncogene

p18Hamlet mediates different p53-Dependent responses to DNA damage inducing agents

Cell Cycle

A new p38 MAP kinase‐regulated transcriptional coactivator that stimulates p53‐dependent apoptosis

EMBO J.

Initiation of a G2/M checkpoint after ultraviolet radiation requires p38 kinase

Nature

The p38 mitogen-activated protein kinase pathway links the DNA mismatch repair system to the G2 checkpoint and to resistance to chemotherapeutic DNA-methylating agents

Mol. Cell. Biol.

Cellular N-Ras promotes cell survival by downregulation of Jun N-terminal protein kinase and p38

Mol. Cell. Biol.

Cancer risk and oxidative DNA damage in man

J. Mol. Med.

Reactive oxygen species: role in the development of cancer and various chronic conditions

J. Carcinog.