Ousting RAGE in melanoma: A viable therapeutic target?

Abstract

Melanoma remains an important health concern, given the steady increase in incidence and acquisition of resistance to systemic therapies. The receptor for advanced glycation end products (RAGE) initially identified for its binding to advanced glycation end products was subsequently acknowledged as a pattern recognition receptor given its ability to recognize similar structural elements within numerous ligands. Recent studies have elucidated a plausible role of RAGE in melanoma progression through modulation of inflammatory, proliferative and invasive cellular responses. Several of its ligands including the S100 proteins and HMGB1 are being investigated for their involvement in melanoma metastasis and as potential biomarkers of the disease. Targeting RAGE signaling represents a viable therapeutic strategy which remains underexplored in cutaneous malignancies. Here we have summarized current knowledge on the functionality of RAGE with special focus on specific ligands enumerated in various in vitro and in vivo melanoma models.

Keywords: AGEs; HMGB1; Melanoma; RAGE; S100 proteins.

Figure 1. RAGE and its isoforms

RAGE forms sRAGE by alternative splicing or proteolytic cleavage from cell surface. flRAGE promotes while sRAGE decreases melanoma progression. flRAGE: full-length RAGE; sRAGE: soluble RAGE

Figure 2. RAGE regulated signaling in melanoma

RAGE induces (i) inflammation through activation of NF-ĸB; secretion of TNFα (ii) promotes angiogenesis (iii) induces melanoma proliferation through IL-23/IL-16/STAT3 activation; upregulation of Akt/ERK1/2/p38 pathways (iv) promotes migration through increase in MMPs; down-regulation of p53, ERK1/2 and NF-ĸB pathways; M2-like macrophage mediated IL-10 production. Red dashed lines show inhibition.