Sirtuin Inhibitor as a Novel Cell Cycle Checkpoint and Regulator of the TP53-MDM2 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 that mitigate metastases the mortality rate is 85% within the first year after detection of the liver disease.
In this study, we provide a mechanistic understanding of the de-regulation of the TP53-MDM2 pathway in UM, which plays a
central role in tumor biology.
Methods
We investigated the TP53-MDM2 signaling pathway in the microenvironment of liver metastases taken from both a murine orthotopic xenograft and post-mortem metastatic UM human liver. These findings were studied in-depth using both primary and
metastatic UM cell lines treated with the MDM2 antagonist Nutlin-3a and the sirtuin inhibitor and transcriptional activator of
TP53, Tenovin-6.
Results
De-regulation of the TP53-MDM2 signaling pathway is specific to the liver microenvironment, providing a survival mechanism
for UM metastases. Tenovin-6, not Nutlin-3a, reduced UM cell survival by increasing the percentage of cell death and reducing
the percentage of proliferating cells. Tenovin-6 increased acetylation of p53, reduced ubiquitination of the protein, and acted as
a cell cycle regulator.
Conclusion
Our findings suggest that in patients with metastatic UM de-regulation of TP53-MDM2 signaling pathway promotes growth of
the liver metastases and provides pre-clinical information on the potential of targeting of the TP53-MDM2 signaling pathway via
Tenovin-6.