Salubrinal in Combination With 4E1RCat Synergistically Impairs Melanoma Development by Disrupting the Protein Synthetic Machinery.

Gregory R Kardos,Raghavendra Gowda,Gavin P Robertson,Saketh Sriram Dinavahi,Scot Kimball

doi:10.3389/fonc.2020.00834

Abstract

Increased protein synthesis is a key process in melanoma, which is regulated by the ALDH18A1 gene encoding pyrroline-5-carboxylate synthase (P5CS). P5CS is involved in proline biosynthesis and targeting ALDH18A1 has previously been shown to inhibit melanoma development by decreasing intracellular proline levels to increase the phosphorylation of eIF2α mediated by GCN2, which then impairs mRNA translation. Since there are no current inhibitors of P5CS, decreased eIF2α phosphorylation in melanoma was targeted using salubrinal (a specific inhibitor of eIF2α phosphatase enzymes). While salubrinal alone was ineffective, the combined use of salubrinal and 4E1RCat (a dual inhibitor of eIF4E:4E-BP1 and eIF4E:eIF4G interaction to prevent assembly of the eIF4F complex and inhibit cap-dependent translation) was found to be effective at decreasing protein synthesis, protein translation, and cell cycle progression to synergistically decrease melanoma cell viability and inhibited xenograft melanoma tumor development. The combination of these agents synergistically decreased melanoma cell viability while having minimal effect on normal cells. This is the first report demonstrating that it is possible to inhibit melanoma viability by targeting eIF2α signaling using salubrinal and 4E1RCat to disrupt assembly of the eIF4F complex.

Highlights

Advancements in our understanding of dysregulated signaling pathways in melanoma have resulted in the development of drugs targeting pathway alterations, such as BRAF and MEK1/2 inhibitors
Since no drugs are available that target alDH18A1, chemical agents disrupting eIF2α or the eIF4F complex were investigated as an approach to target this pathway
As the protein synthesis machinery has been reported as an important component downstream of signaling cascades disrupted in melanoma [11], the identification of agents to target this pathway could assist in overcoming resistance

Summary

Introduction

Advancements in our understanding of dysregulated signaling pathways in melanoma have resulted in the development of drugs targeting pathway alterations, such as BRAF and MEK1/2 inhibitors. These inhibitors have improved patient care, resistant disease eventually develops. The PI3K/AKT pathway is activated in many melanoma cases, which can impair apoptosis and promote cell proliferation [6, 7]. These pathways converge to increase protein production, by regulating translational initiation [8,9,10,11]. Translation initiation signaling has been identified as a promising pathway for therapeutic targeting

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Conclusion