Metastatic melanoma is notoriously difficult to treat. Although treatment options have improved with the introduction of new targeted therapies and immunotherapies, more therapeutic strategies are needed. Rab27a (member of the Rab GTPase protein trafficking family) has increased expression in melanoma cells compared to benign nevi and has been identified as a potential driver gene in a study of chromosomal copy number and gene expression in melanoma. In melanocytes Rab27a regulates pigment granule trafficking. The function of Rab27a in melanoma cell biology is poorly understood.
In order to investigate the function of Rab27a in melanoma, shRNA knockdown of Rab27a in Rab27a-high melanoma cell lines was performed. Loss of Rab27a inhibited proliferation and invasion in a 3D spheroid assay. This decrease in invasion may be due to loss of invadopodia formation. Rab27a-GFP fusion proteins were transfected into melanoma cells to determine intracellular localization. Rab27a-GFP localized to melanosomes and non-melanosomal structures, including actin rich foci, supporting a role for Rab27a in invadopodia formation.
Treatment of melanoma cells with simvastatin, which is a non-specific inhibitor of Rab function, inhibited invasion at low concentrations, while high concentrations caused cell death. Invasion was more substantially inhibited in Rab27a-high cell lines, suggesting inhibition of Rab27a may partially explain the effect of statins on melanoma invasion.
Our data indicate that Rab27a plays a central role in proliferation and invasion in Rab27a-high melanoma cells. Rab27a expression is confined to melanocytic cells as well as some other specialized cell types making Rab27a a novel potential therapeutic target. Although no specific Rab inhibitors are available, statins, which are commonly used to treat hypercholesterolemia, are known to inhibit the function of small GTPases such as Rabs. At clinically relevant low concentrations, statins were able to reduce melanoma invasion. Statins may thus be a safe preventative therapy in high-risk individuals or early stage melanoma for preventing melanoma metastasis, and future development of more specific Rab27a inhibitors may also have therapeutic potential.