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.

Keywords: Melanoma; Mitochondria; NADPH oxidase; Nox1; Nox4; RNS; ROS; Reactive oxygen species.

Figure 1. The source of ROS in melanocytes and their cellular effect

ROS can be generated from melanosomes, mitochondria, NOX family enzymes and/or NOS uncoupling. ROS generated from these different sources may interact with each other and form a cellular ROS pool. When ROS levels are adequate, they serve as proliferation signals; when ROS is raised, they show adverse effect including promoting invasion and DNA oxidative mutations. If ROS level is beyond the cellular antioxidant buffering capacity, they can directly kill cells.