Sirtuin Inhibitor as a Novel Cell Cycle Checkpoint and Regulator of the TP53-MDM2 Pathway in Uveal Melanoma

*Corresponding author: Zachary K. Goldsmith, Matthew W. McEwen, Mercy W. Kibe, Kelley Yuan, Hua Yang, Qing Zhang, Sumana R. Chintalapudi, Bradley T. Gao, Monica M. Jablonski, Benjamin King, Ryan P. Lee, Abigail Lepsch, Neel Patel, Xiang Di Wang, Hans E. Grossniklaus, Matthew W. Wilson*, Vanessa M. Morales-Tirado*

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original research

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.

Keywords

Uveal melanoma; Ocular tumors; Nutlin-3a; Tenovin-6; TP53; MDM2.