RAGE Signaling in Melanoma Tumors

Abstract

Despite recent progresses in its treatment, malignant cutaneous melanoma remains a cancer with very poor prognosis. Emerging evidences suggest that the receptor for advance glycation end products (RAGE) plays a key role in melanoma progression through its activation in both cancer and stromal cells. In tumors, RAGE activation is fueled by numerous ligands, S100B and HMGB1 being the most notable, but the role of many other ligands is not well understood and should not be underappreciated. Here, we provide a review of the current role of RAGE in melanoma and conclude that targeting RAGE in melanoma could be an approach to improve the outcomes of melanoma patients.

Keywords: HMGB1; RAGE; S100 proteins; inflammation; melanoma; melanomagenesis; receptor for advanced glycation end products; tumorigenesis.

Figure 1

Schematic representation of membrane-bound full-length receptor for advance glycation end products (RAGE) and soluble RAGE (sRAGE). (A) Full-length RAGE consists of three extracellular domains (variable domain (V), constant domain 1 (C1), and constant domain 2 (C2)), a single transmembrane domain, and a short cytoplasmic tail. Short spacer sequences are present between the different domains. (B) sRAGE is formed by the extracellular domains only and lacks the transmembrane domain and the cytoplasmic tail.

Figure 2

Possible dimeric and oligomeric forms of RAGE. (A) RAGE dimers have been suggested to be required for signal transduction [104]; in this representation, all three extracellular domains and the transmembrane domain are involved in dimer formation. (B) Dimerization via the V domain only [112]. (C) Models for the inhibitory RAGE/sRAGE heterodimer [113]. (D) Ligand-induced RAGE homodimers [105]. (E) Dimerization via the V domain of RAGE between two different cells [114]. (F) Dimerization through a ligand bound to two C2 domains [115]. (G,H) Other oligomeric forms of RAGE have been proposed as well (tetramers and hexamers) [105].

Figure 3

RAGE signaling pathways. The C-terminus cytoplasmic tail of RAGE is crucial to RAGE signaling. Two adaptor proteins interacting with the cytoplasmic tail of RAGE have been identified: Dia-1 and TIRAP [233,234]. RAGE activation leads to increased cell migration through the activation of several members of the Rho family of small GTPases, including RhoA, Cdc42, and Rac-1 [230,233]. The signaling cascades of these proteins (Dia-1/RhoA; Dia-1/Cdc42/Wiskott-Aldrich syndrome protein (WASP)/actin related protein (Arp); Dia-1/Rac/WASP family verprolin-homologous protein-2 (WAVE2)/Arp) lead to actomyosin contractility and actin polymerization [235]. Similarly, RAGE-mediated activation of Janus kinase (JAK) leads to the downstream phosphorylation of Signal transducer and activator of transcription (STAT)3 and its subsequent dimerization resulting in gene transcription [236,237]. Additionally, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase can be activated, leading to ROS generation, which leads to NF-κB activation [238]. RAGE/PI3K/AKT, RAGE/MAPK/c-JUN, RAGE/MAPK/p38, and RAGE/MAPK/Extracellular signal-related kinase (ERK) axes can also result in the activation of NF-κB [239,240,241]. In addition to NF-κB, RAGE has also been shown to signal through AP-1 and cyclic AMP response element-binding protein (CREB) [242,243,244].