Ferroptosis: a new unexpected chance to treat metastatic melanoma?

Abstract

Human skin melanoma is one of the most aggressive and difficult to treat human malignancies, with an increasing incidence over the years. While the resection of the early diagnosed primary tumor remains the best clinical approach, advanced/metastatic melanoma still remains with a poor prognosis. Indeed, although enormous progress in the therapeutic treatment of human tumors has been made in recent years, patients affected by metastatic melanoma are still poorly affected by these clinical advances. Therefore, new valuable therapeutic approaches are urgently needed, to design and define effective treatments to consistently increase the overall survival rate of patients affected by this malignancy. In this review we summarize the main signaling pathways studied to kill human skin melanoma, and introduce the ferroptotic cell death as a new pathway to be explored to eradicate this tumor.

Keywords: AKR; Ferroptosis; NRF2; lipid-ROS; melanoma.

Figure 1.

Ferroptosis. The key players of the ferroptotic cell death process have been highlighted. AKRs = Aldo-keto reductases; Cys = cysteine; FTH1 = Ferritin heavy chain 1; FTL = Ferritin light chain; GSH = Glutathione; GSSG = Oxidized Glutathione; GPX4 = Glutathione peroxidase 4; LOX = Lipoxygenases; PUFAs = Polyunsaturated fatty acids; TFR1 = Transferrin receptor 1; ERA = Erastin; Fer-1 = Ferrostatin-1; MPA = Medroxyprogesterone; RLS3 = Ras-selective lethal small molecule 3; SOR = Sorafenib.

Figure 2.

AKRs expression in primary tumor-derived melanoma. The expression of AKR1C1÷ C3 was evaluated in the “Graber cohort” of melanoma cells directly derived by primary tumors (https://systems.crump.ucla.edu/dediff/index.php). This interpolation shows that the three enzymes seem to be preferentially expressed in the less differentiated cell types, especially the AKR1C3.

Figure 3.

Melanoma development, progression and Ferroptosis susceptibility. Melanocytes are cells located in the stratum basale (a) of the skin’s epidermis, the uvea, the inner ear, meninges, vaginal epithelium, heart, and bones. They are neural crest-derived cells producing melanin, a dark pigment responsible for skin color and protection from UV light. Upon transformation, melanocytes start to grow, giving rise to the primary tumor (b). At this stage, melanoma cells display a heterogeneous grade of differentiation which correlates to Ferroptosis susceptibility. In the advanced stages, the loose of intercellular junctions and the rupture of the basal lamina allow cancer cells to invade the underlying dermis, which reaching the blood and lymphatic circuits (c) will allow them to give rise to metastases (d). Ex vivo data indicate that basal expression of AKRs seems to be not predictive of Ferroptosis sensitivity while AKRs upregulation/activation (2) in pro-ferroptotic (1) treated metastatic cells does. Indeed, if no AKRs activation/upregulation is observed, metastatic melanoma cells are efficiently killed by Ferroptosis execution (3). On the other hand, AKRs upregulation/activation will result in ferroptosis inhibition and failure of treatment. However, combined pro-ferroptotic drugs with AKRs inhibitor will efficiently increase cancer cell death through effective Ferroptosis execution (5).