Redox pathways in melanoma

Abstract

Cases of melanoma are doubling every 12 years, and in stages III and IV, the disease is associated with high mortality rates concomitant with unresectable metastases and therapeutic drug resistance. Despite some advances in treatment success, there is a marked need to understand more about the pathology of the disease. The present review provides an overview of how melanoma cells use and modulate redox pathways to facilitate thiol homeostasis and melanin biosynthesis and describes plausible redox targets that may improve therapeutic approaches in managing malignant disease and metastasis. Melanotic melanoma has some unique characteristics. Making melanin requires a considerable dedication of cellular energy resources and utilizes glutathione and glutathione transferases in certain steps in the biosynthetic pathway. Melanin is an antioxidant but is also functionally important in hematopoiesis and influential in various aspects of host immune responses, giving it unique characteristics. Together with other redox traits that are specific to melanoma, a discussion of possible therapeutic approaches is also provided.

Keywords: Glutathione; Melanin; Melanoma; Microsomal glutathione transferase; Redox homeostasis.

Fig. 1

GST/GSH involvement in melanin biosynthesis. Pheomelanin and eumelanin are synthesized from the amino acid tyrosine, with dopaquinone as an intermediate metabolite, catalyzed by tyrosinase (TYR). Quinones are electrophilic species and the formation of a GSH-dopaquinone conjugate, catalyzed by GSTP and GSTM2–2, serves both to “detoxify” and create an intermediate in melanin synthesis. Sequential in the biosynthesis, gamma-glutamyl transpeptidase (GGT) and aminopeptidase N (APN) remove two of the GSH amino acids to leave cysteinyldopa, a catecholamine. In addition to the pheomelanin pathway, dopaquinone can undergo slow intramolecular cyclization to cyclodopa, followed by rapid oxidation to dopachrome, the precursor of eumelanin. In the step shown, MGST1 may operate as a cyclase by stabilization of the deprotonated dopaquinone.

Fig. 2

Knockdown of mgst1 expression suppresses melanin synthesis (A), hemoglobin contents (B), red blood cell numbers (C), and myeloid and lymphoid differentiation (D) in zebrafish.

Fig. 3

Knockdown (KD) of Mgst1 was shown to enhance the efficacy of chemotherapy and immunotherapy in B16 melanotic melanomas. (A) and (B) Co-culture of melanoma cells with regular and gp100 activated Pmel T cells. (C–E) Enhanced cellular sensitivity to cytotoxic anticancer drugs and ferroptotic cell death. ND, not detectable. (F) Elevated expression of chemokine levels in Mgst1 KD B16 cells.