July 2018
Volume 59, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2018
The Sirtuin Inhibitor Tenovin-6 as a Novel Regulator of the TP53-MDM2 Signaling Pathway in Uveal Melanoma
Author Affiliations & Notes
  • Matthew W Wilson
    Ophthalmology, Hamilton Eye Institute, University of Tennessee Health Science Center, Memphis, Tennessee, United States
    Surgery, St. Jude Children's Research Hospital, Memphis, Tennessee, United States
  • Matthew W McEwen
    Ophthalmology, Hamilton Eye Institute, University of Tennessee Health Science Center, Memphis, Tennessee, United States
  • Zachary K. Goldsmith
    Ophthalmology, Hamilton Eye Institute, University of Tennessee Health Science Center, Memphis, Tennessee, United States
  • Kelley Yuan
    Ophthalmology, Hamilton Eye Institute, University of Tennessee Health Science Center, Memphis, Tennessee, United States
  • Andrew Irvine
    Ophthalmology, Hamilton Eye Institute, University of Tennessee Health Science Center, Memphis, Tennessee, United States
  • Benjamin King
    Ophthalmology, Hamilton Eye Institute, University of Tennessee Health Science Center, Memphis, Tennessee, United States
  • Hua Yang Yang
    Ophthalmology, Emory University, Atlanta, Georgia, United States
  • Hans Grossniklaus
    Ophthalmology, Emory University, Atlanta, Georgia, United States
  • Vanessa Marie Morales-Tirado
    Ophthalmology, Hamilton Eye Institute, University of Tennessee Health Science Center, Memphis, Tennessee, United States
    Microbiology, Immunology, and Biochemistry, University of Tennessee Health Science Center, Memphis, Tennessee, United States
  • Footnotes
    Commercial Relationships   Matthew Wilson, None; Matthew McEwen, None; Zachary Goldsmith, None; Kelley Yuan, None; Andrew Irvine, None; Benjamin King, None; Hua Yang, None; Hans Grossniklaus, None; Vanessa Morales-Tirado, None
  • Footnotes
    Support  Research to Prevent Blindness, West Cancer Center, NIH NCI R01CA76001, NIH Medical Student Summer Research Fellowship, SJCRH, The Neuroscience Institute at UTHSC, Gerwin Fellowship
Investigative Ophthalmology & Visual Science July 2018, Vol.59, 3175. doi:
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      Matthew W Wilson, Matthew W McEwen, Zachary K. Goldsmith, Kelley Yuan, Andrew Irvine, Benjamin King, Hua Yang Yang, Hans Grossniklaus, Vanessa Marie Morales-Tirado; The Sirtuin Inhibitor Tenovin-6 as a Novel Regulator of the TP53-MDM2 Signaling Pathway in Uveal Melanoma. Invest. Ophthalmol. Vis. Sci. 2018;59(9):3175.

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      © ARVO (1962-2015); The Authors (2016-present)

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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.

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