In Uveal Melanoma, Sirtuin Inhibitor as a New Cell Cycle Checkpoint and TP53-MDM2 Pathway Regulator

Authors

  • Zachary K. Goldsmith Department of Ophthalmology, Hamilton Eye Institute,The University of Tennessee Health Science Center, Memphis,TN, USA
  • Matthew W. McEwen Department of Ophthalmology, Hamilton Eye Institute,The University of Tennessee Health Science Center, Memphis,TN, USA
  • Mercy W. Kibe Department of Ophthalmology, Hamilton Eye Institute,The University of Tennessee Health Science Center, Memphis,TN, USA
  • Kelley Yuan Department of Ophthalmology, Hamilton Eye Institute,The University of Tennessee Health Science Center, Memphis,TN, USA
  • Hua Yang Department of Ophthalmology, Emory Eye Center, Emory University, Atlanta, GA, USA
  • Qing Zhang Department of Ophthalmology, Emory Eye Center, Emory University, Atlanta, GA, USA
  • Sumana R. Chintalapudi Department of Ophthalmology, Hamilton Eye Institute,The University of Tennessee Health Science Center, Memphis,TN, USA
  • Bradley T. Gao Department of Ophthalmology, Hamilton Eye Institute,The University of Tennessee Health Science Center, Memphis,TN, USA
  • Monica M. Jablonski Department of Ophthalmology, Hamilton Eye Institute,The University of Tennessee Health Science Center, Memphis,TN, USA; Department of Anatomy and Neurobiology,The University of Tennessee Health Science Center, Memphis,TN, USA; Department of Pharmaceutical Sciences,The University of Tennessee Health Science Center, Memphis,TN, USA
  • Benjamin King Department of Ophthalmology, Hamilton Eye Institute,The University of Tennessee Health Science Center, Memphis,TN, USA
  • Ryan P. Lee Department of Ophthalmology, Hamilton Eye Institute,The University of Tennessee Health Science Center, Memphis,TN, USA
  • Abigail Lepsch Department of Ophthalmology, Hamilton Eye Institute,The University of Tennessee Health Science Center, Memphis,TN, USA
  • Neel Patel Department of Ophthalmology, Hamilton Eye Institute,The University of Tennessee Health Science Center, Memphis,TN, USA
  • Xiang Di Wang Department of Ophthalmology, Hamilton Eye Institute,The University of Tennessee Health Science Center, Memphis,TN, USA
  • Hans E. Grossniklaus Department of Ophthalmology, Emory Eye Center, Emory University, Atlanta, GA, USA
  • Matthew W. Wilson Department of Ophthalmology, Hamilton Eye Institute,The University of Tennessee Health Science Center, Memphis,TN, USA; Department of Surgery, St. Jude Children’s Research Hospital, Memphis,TN, USA
  • Vanessa M. Morales-Tirado Department of Ophthalmology, Hamilton Eye Institute,The University of Tennessee Health Science Center, Memphis,TN, USA; Department of Microbiology, Immunology and Biochemistry,The University of Tennessee Health Science Center, Memphis,TN, USA

Keywords:

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

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.

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Published

2024-12-18

How to Cite

Zachary K. Goldsmith, Matthew W. McEwen, Mercy W. Kibe, Kelley Yuan, Hua Yang, Qing Zhang, … Vanessa M. Morales-Tirado. (2024). In Uveal Melanoma, Sirtuin Inhibitor as a New Cell Cycle Checkpoint and TP53-MDM2 Pathway Regulator. The Ophthalmology, 21–30. Retrieved from https://openventio.us/index.php/TOOJ/article/view/1178

Issue

Volume 7 Issue 1 2024

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