ROS as Regulators of Cellular Processes in Melanoma.

Isabella Venza,Francesco Stagno d'Alcontres,Diana Teti,Germana Lentini,Maria Visalli,Mario Venza,Javier Egea

doi:10.1155/2021/1208690

Isabella Venza, Francesco Stagno d'Alcontres + Show 5 more

Open Access

https://doi.org/10.1155/2021/1208690

Copy DOI

Abstract

In this review, we examine the multiple roles of ROS in the pathogenesis of melanoma, focusing on signal transduction and regulation of gene expression. In recent years, different studies have analyzed the dual role of ROS in regulating the redox system, with both negative and positive consequences on human health, depending on cell concentration of these agents. High ROS levels can result from an altered balance between oxidant generation and intracellular antioxidant activity and can produce harmful effects. In contrast, low amounts of ROS are considered beneficial, since they trigger signaling pathways involved in physiological activities and programmed cell death, with protective effects against melanoma. Here, we examine these beneficial roles, which could have interesting implications in melanoma treatment.

Highlights

It has become increasingly evident in recent years that the production of reactive oxygen species (ROS) is involved in the regulation of normal cell functions and that its dysregulation can be responsible for the onset of harmful events [1]
Cystein oxidation may reversibly modulate the functions of some proteins, as shown in the following examples: (i) the inactivation of the catalytic site of protein tyrosine phosphatase SHP-2 induced by high concentrations of H2O2 allows plateletderived growth factor (PDGF) to activate MAPK signaling [33,34,35], (ii) the p38 mitogen-activated protein kinase (MAPK) signaling pathway is activated in association with conformational modifications of the disulfide reductase thioredoxin (Trx) that leads to the release of the complexed protein apoptosis stimulating kinase 1 (ASK1) [36, 37], (iii) HOCl regulates the activity of matrix metalloprotease 7 (MMP-7) by oxidation of cystein residues in proenzyme metalloprotease 7 in vitro [38], and (iv) cystein oxidation increases the activity of the cell redox sensor Ca2+-release channels in heart and skeletal muscle in vitro [39, 40]
The specificity of ROS on diverse signaling pathways depends on the pKa of signaling molecules, the redox status around the signaling pathway, and the total redox status in the cell [122]. Both extracellular ROS, as hydrogen peroxide, or oxidants produced within the cells, as superoxide anion, may act as second messengers in signaling transduction systems and in regulating pathways sensitive to the redox status [5, 123]. Such pathways involve signaling molecules, including p38/mitogen activated protein kinases (MAPKs), phosphatidyl inositol-3 kinase (PI3K)/Akt [124, 125], various protein kinase C (PKC) family members, and c-Jun N-terminal kinase (JNK) [126, 127], that are modulated by nicotinamide adenine dinucleotide phosphate hydrogen (NADPH) oxidase and pathway-specific transcription factors such as nuclear factor-κB (NF-κB) [128], activator protein 1 (AP-1), hypoxia inducible factor (HIF), and p53

Summary

Introduction

It has become increasingly evident in recent years that the production of reactive oxygen species (ROS) is involved in the regulation of normal cell functions and that its dysregulation can be responsible for the onset of harmful events [1]. Mitochondrial biogenesis and proper mitochondrial function are essential to maintain physiological ROS levels and prevent the detrimental effects deriving from excessive ROS production Such activity has great relevance in cell biology, since mitochondrial DNA is exposed to unbalanced ROS generation from both environmental and nutritive factors and is highly sensitive to oxidative damage. Oxidative posttranslational modifications (Ox-PTM) represent a switch able to change protein structure and function, including the catalytic properties of enzymes [27, 28] In this regard, the thiol (RSH) functional group of cysteine residues within proteins represents the major cellular ROS target, especially of H2O2 and superoxide anion [29]. Cystein oxidation may reversibly modulate the functions of some proteins, as shown in the following examples: (i) the inactivation of the catalytic site of protein tyrosine phosphatase SHP-2 induced by high concentrations of H2O2 allows PDGF to activate MAPK signaling [33,34,35], (ii) the p38 mitogen-activated protein kinase (MAPK) signaling pathway is activated in association with conformational modifications of the disulfide reductase thioredoxin (Trx) that leads to the release of the complexed protein apoptosis stimulating kinase 1 (ASK1) [36, 37], (iii) HOCl regulates the activity of matrix metalloprotease 7 (MMP-7) by oxidation of cystein residues in proenzyme metalloprotease 7 in vitro [38], and (iv) cystein oxidation increases the activity of the cell redox sensor Ca2+-release channels (ryanodinereceptors) in heart and skeletal muscle in vitro [39, 40]

Antioxidant Enzymatic Systems

Concluding Remarks