The Sirtuin Inhibitor Tenovin-6 as a Novel Regulator of the TP53-MDM2 Signaling Pathway in Uveal Melanoma

Abstract

Purpose : The liver is the most common site of uveal melanoma (UM) metastasis with approximately 50% of UM patients being affected. With no proven therapies, there is a mortality rate of 85% within the first year. The purpose of this study is to provide a comprehensive analysis of the TP53-MDM2 pathway in UM.

Methods : We investigate the TP53-MDM2 signaling pathway in a murine orthotopic xenograft and post-mortem metastatic UM human liver. Mechanistic studies were addressed on both primary and metastatic UM cell lines treated with the MDM2 agonist Nutlin-3a and the sirtuin inhibitor and transcriptional activator of TP53, Tenovin-6.

Results : In vivo and ex vivo studies demonstrated differences between UM cells prior to inoculation and after seeding into the liver microenvironment. In vitro studies showed Tenovin-6, not Nutlin-3a, reduced tumor cell growth and survival by increasing cell death and reducing the percentage of cells going through the G2/M cell cycle phase.

Conclusions : The TP53-MDM2 signaling pathway is de-regulated in metastatic UM as a result of both functional inactivation and inhibition of TP53.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.