UC2288 decreases the viability and metastatic activity of human Uveal melanoma cells via activating the AMPK/eIF2/ATF4 ER stress axis.

Uveal melanoma (UM) is the primary intraocular malignancy in adults and has an extremely poor prognosis due to a high rate of metastasis. Because current drug options are generally ineffective, there is an urgent need for new agents with anti-UM efficacy. The phenylcyclohexyl-urea UC2288 was investigated in in vitro, ex vivo and in vivo UM models. The anti-cancer actions of UC2288 were evaluated using cell viability and cell death assays. Tumour migration, invasion and reproductive cell growth assays were used to assess the anti-metastatic potential of UC2288. Such effects were corroborated in primary cultures derived from patient tumours and in vivo in a UM cell xenograft mouse model. UC2288 decreased UM cell proliferation in conventional and 3-dimensional cell culture by disrupting cell cycle progression and modulating cyclin expression. UC2288 also targeted the mitochondrion and increased the production of reactive oxygen species, which promoted necrotic cell death. In mechanistic studies, UC2288 activated AMPK and downstream eIF2/ATF pathways of ER stress and autophagy in UM cells. UC2288 also impaired UM cell migration, invasion and reproductive growth, which is consistent with anti-metastatic activity. These findings were replicated in vivo in a UM cell xenograft model. Taken together, UC2288 represents a promising candidate for further development that targets UM tumours with favourable anti-cancer effects.