Targeting the mercapturic acid pathway for the treatment of melanoma

The treatment of metastatic melanoma is greatly hampered by the simultaneous dysregulation of several major signaling pathways that suppress apoptosis and promote its growth and invasion. The global resistance of melanomas to therapeutics is also supported by a highly active mercapturic acid pathway (MAP), which is responsible for the metabolism and excretion of numerous chemotherapy agents. The relative importance of the MAP in melanoma survival was not recognized until demonstrated that B16 melanoma undergoes dramatic apoptosis and regression upon the depletion or inhibition of the MAP transporter protein RLIP. RLIP is a multi-functional protein that couples ATP hydrolysis with the movement of substances. As the rate-limiting step of the MAP, the primary function of RLIP in the plasma membrane is to catalyze the ATP-dependent efflux of unmetabolized drugs and toxins, including glutathione (GSH) conjugates of electrophilic toxins (GS-Es), which are the precursors of mercapturic acids. Clathrin-dependent endocytosis (CDE) is an essential mechanism for internalizing ligand-receptor complexes that promote tumor cell proliferation through autocrine stimulation (Wnt5a, PDGF, βFGF, TNFα) or paracrine stimulation by hormones produced by fibroblasts (IGF1, HGF) or inflammatory cells (IL8). Aberrant functioning of these pathways appears critical for melanoma cell invasion, metastasis, and evasion of apoptosis. This review focuses on the selective depletion or inhibition of RLIP as a highly effective targeted therapy for melanoma that could cause the simultaneous disruption of the MAP and critical peptide hormone signaling that relies on CDE.