June 2015
Volume 56, Issue 7
Free
ARVO Annual Meeting Abstract  |   June 2015
Modulation of Cytoskeletal Associated Proteins Regulates Cell Death and Survival in Uveal Melanoma
Author Affiliations & Notes
  • Matthew W Wilson
    Ophthal/Hamilton Eye Int, Univ of Tennessee Health Sci Ctr, Memphis, TN
    Surgery, St Jude Children's Research Hospital, Memphis, TN
  • Ryan P Lee
    Ophthal/Hamilton Eye Int, Univ of Tennessee Health Sci Ctr, Memphis, TN
  • Sumana R Chintalapudi
    Ophthal/Hamilton Eye Int, Univ of Tennessee Health Sci Ctr, Memphis, TN
  • Bradley T Gao
    Ophthal/Hamilton Eye Int, Univ of Tennessee Health Sci Ctr, Memphis, TN
  • Justin B Lendermon
    Ophthal/Hamilton Eye Int, Univ of Tennessee Health Sci Ctr, Memphis, TN
  • Nabil Saleh
    Ophthal/Hamilton Eye Int, Univ of Tennessee Health Sci Ctr, Memphis, TN
  • Anderson Hudgens Webb
    Ophthal/Hamilton Eye Int, Univ of Tennessee Health Sci Ctr, Memphis, TN
  • Hans E Grossniklaus
    Emory Eye Center, Eye Univeristy, Atlanta, GA
  • Vanessa Marie Morales
    Ophthal/Hamilton Eye Int, Univ of Tennessee Health Sci Ctr, Memphis, TN
    Microbiology, Immunology and Biochemistry, University of Tennessee Health Science Center, Memphis, TN
  • Footnotes
    Commercial Relationships Matthew Wilson, None; Ryan Lee, None; Sumana Chintalapudi, None; Bradley Gao, None; Justin Lendermon, None; Nabil Saleh, None; Anderson Webb, None; Hans Grossniklaus, None; Vanessa Morales, None
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science June 2015, Vol.56, 4332. doi:https://doi.org/
  • Views
  • Share
  • Tools
    • Alerts
      ×
      This feature is available to authenticated users only.
      Sign In or Create an Account ×
    • Get Citation

      Matthew W Wilson, Ryan P Lee, Sumana R Chintalapudi, Bradley T Gao, Justin B Lendermon, Nabil Saleh, Anderson Hudgens Webb, Hans E Grossniklaus, Vanessa Marie Morales; Modulation of Cytoskeletal Associated Proteins Regulates Cell Death and Survival in Uveal Melanoma. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):4332. doi: https://doi.org/.

      Download citation file:


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

      ×
  • Supplements
Abstract

Purpose: Purpose: Approximately 50% of Uveal Melanoma (UM) patients will be diagnosed with liver metastases within 5-years of diagnosis. Micro-metastases are present in the liver as early as 2-years before diagnosis of the intraocular malignancy. Recent work from our laboratory suggests that inhibiting the upregulation of cytoskeletal signaling could offer potential therapeutic targets for metastasis control. In this study we elucidate the mechanism(s) involved.

Methods: Methods: We performed gene transcription, flow cytometry as well as cellular and molecular biology analyses after pharmacological modulation of paxillin Y118 using the paxillin inhibitor 6-B345TTQ. The effects of paxillin inhibition (pY118) were measured on pAKT, Protein Kinase C-delta (PKC-δ), pro-apoptotic molecules expression, actin polymerization and cellular proliferation in UM cell lines and immunohistochemical (IHC) analyses in normal and with UM. We performed cutting edge Nano3D (Nano 3D Biosciences Inc, Houston, TX) technology to investigate changes in cellular migration and proliferation after paxillin inhibition.

Results: Results: We observed an increase in the alpha-4 subunit of VLA-4 and paxillin both in the UM cell lines by flow cytometry analysis (p<0.05) and in UM eyes compared to normal eyes by IHC. Targeting of paxillin through inhibition of pY118 reduced cellular proliferation in primary, not metastatic, UM. Mechanistically, we observed a significant reduction in pAKT signaling in metastatic UM (p<0.05) by Western blot analysis and phospho-PKC-δ in the metastatic UM cell lines by flow cytometry. IHC analysis in human eyes revealed differences in PKC-δ expression in normal and UM eyes.

Conclusions: Conclusions: Our in vitro results identified paxillin as a potential therapeutic target to arrest UM cellular proliferation and migration. Inhibition of paxillin preferentially affected primary UM cells compared to metastatic cell lines through pAKT and PKC-δ and may represent a potential targeted therapy for micrometastases.

×
×

This PDF is available to Subscribers Only

Sign in or purchase a subscription to access this content. ×

You must be signed into an individual account to use this feature.

×