Updates of reactive oxygen species in melanoma etiology and progression

Abstract

Reactive oxygen species (ROS) play crucial roles in all aspects of melanoma development, however, the source of ROS is not well defined. In this review we summarize recent advancement in this rapidly developing field. The cellular ROS pool in melanocytes can be derived from mitochondria, melanosomes, NADPH oxidase (NOX) family enzymes, and uncoupling of nitric oxide synthase (NOS). Current evidence suggests that Nox1, Nox4 and Nox5 are expressed in melanocytic lineage. While there is no difference in Nox1 expression levels in primary and metastatic melanoma tissues, Nox4 expression is significantly higher in a subset of metastatic melanoma tumors as compared to the primary tumors; suggesting distinct and specific signals and effects for NOX family enzymes in melanoma. Targeting these NOX enzymes using specific NOX inhibitors may be effective for a subset of certain tumors. ROS also play important roles in BRAF inhibitor induced drug resistance; hence identification and blockade of the source of this ROS may be an effective way to enhance efficacy and overcome resistance. Furthermore, ROS from different sources may interact with each other and interact with reactive nitrogen species (RNS) and drive the melanomagenesis process at all stages of disease. Further understanding ROS and RNS in melanoma etiology and progression is necessary for developing new prevention and therapeutic approaches.

Glutathione peroxidase 3 (GPX3) suppresses the growth of melanoma cells through reactive oxygen species (ROS)‐dependent stabilization of hypoxia‐inducible factor 1‐α and 2‐α

“…Our study also documented an increase of ROS in MM tissues and cells. It is reported that melanoma is a ROS‐driven tumor, and ROS played important roles in all aspects of melanoma development . Cancer cells including melanoma cells were reported to show high levels of ROS .…”

NADPH oxidase 5 (NOX5)—induced reactive oxygen signaling modulates normoxic HIF‐1α and p27Kip1 expression in malignant melanoma and other human tumors

“…Much recent research has focused on how low levels of intracellular ROS (10‐100 nM) regulate tumor growth by facilitating mutagenesis, tumor initiation, and tumor promotion . Members of the NAPDH oxidase (NOX) family play a major role in generating ROS in a broad range of cell types . This 7‐membered family is comprised of NOXes 1‐5 and DUOX 1 and 2 proteins that function to generate ROS by oxidizing NADPH to NADP + .…”

Reprogramming human A375 amelanotic melanoma cells by catalase overexpression: Upregulation of antioxidant genes correlates with regression of melanoma malignancy and with malignant progression when downregulated

“…Disruption of the normal redox balance by deregulation in AOS proteins, such as superoxide dismutase (SOD), catalase and glutathione and thioredoxin system proteins, was associated with cancer development [10–13]. Dysfunction of ROS-producing systems coevolves with the AOS to a new redox balance leading to the progression from melanocytes to melanoma [14]. Besides, the prooxidant state in melanoma may also induce alterations in proteins involved either in melanogenesis or metastasis.…”