June 2020
Volume 61, Issue 7
Open Access
ARVO Annual Meeting Abstract  |   June 2020
Cysteinyl leukotriene receptor 1 (CysLT1) is associated with clinical parameters of uveal melanoma and CysLT receptor antagonists inhibit cancer hallmarks in vitro and in vivo
Author Affiliations & Notes
  • Kayleigh Slater
    Biomolecular and Biomedical Science , University College Dublin, Dublin 4, Dublin, Ireland
  • Aisling Heeran
    Trinity College Dublin, Ireland
  • Mays Helmi
    Linkoping University, Sweden
  • Helen Kalirai
    University of Liverpool, United Kingdom
  • Sarah E Coupland
    University of Liverpool, United Kingdom
  • Alberto Villanueva
    Xenopat, Spain
  • Rosa Bosch
    Xenopat, Spain
  • Lasse Jensen
    Linkoping University, Sweden
  • Josep Piulats
    IDIBELL Bellvitge Biomedical Research Institute, Spain
  • Jacintha O'Sullivan
    Trinity College Dublin, Ireland
  • Breandan N Kennedy
    Biomolecular and Biomedical Science , University College Dublin, Dublin 4, Dublin, Ireland
  • Footnotes
    Commercial Relationships   Kayleigh Slater, None; Aisling Heeran, None; Mays Helmi, None; Helen Kalirai, None; Sarah Coupland, None; Alberto Villanueva, Xenopat (E); Rosa Bosch, Xenopat (E); Lasse Jensen, None; Josep Piulats, None; Jacintha O'Sullivan, Trinity College Dublin (P); Breandan Kennedy, University College Dublin (P)
  • Footnotes
    Support  Irish Research Council EBP.2017.473
Investigative Ophthalmology & Visual Science June 2020, Vol.61, 2849. doi:
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      Kayleigh Slater, Aisling Heeran, Mays Helmi, Helen Kalirai, Sarah E Coupland, Alberto Villanueva, Rosa Bosch, Lasse Jensen, Josep Piulats, Jacintha O'Sullivan, Breandan N Kennedy; Cysteinyl leukotriene receptor 1 (CysLT1) is associated with clinical parameters of uveal melanoma and CysLT receptor antagonists inhibit cancer hallmarks in vitro and in vivo. Invest. Ophthalmol. Vis. Sci. 2020;61(7):2849.

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

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Abstract

Purpose : Cysteinyl leukotriene receptor dysregulation is associated with a poor prognosis in various cancers. Additionally, CYSLTR2 is a uveal melanoma (UM) oncogene in 4% of patients. This research investigates the expression and tumorigenic nature of the G-protein coupled cysteinyl leukotriene receptors (CysLT1 and CysLT2) in UM and explores their potential as therapeutic targets.

Methods : Western blot and qPCR examined expression of both receptors in primary and metastatic UM cell lines (n≥3) Mel285, Mel270 and OMM2.5. Immunohistochemical staining on UM patient samples (n = 50) analysed expression of both receptors and their relationship to matched patient clinical data. The effect of cysteinyl leukotriene receptor targeting drugs (10 - 50 μM) on UM cell survival and proliferation (n≥3) was analysed. The three highest-ranking drugs were tested in zebrafish cell line xenograft models and Seahorse metabolism assays to elucidate their effects on cancer hallmarks.

Results : CysLT1 and CysLT2 are expressed in all UM cell lines and patient tumours analysed. Interestingly, high CysLT1 expression has a statistically significant association with ciliary body involvement (p =0.041), a poor prognostic indicator in the disease. Similarly, this receptor showed a trend towards high expression and poor patient survival but did not reach statistical significance (p = 0.122). Drugs that specifically target CysLT1, but not those targeting CysLT2, significantly block long-term cell proliferation and inhibit oxidative phosphorylation, but not glycolysis, in a variety of UM cell lines or zebrafish xenograft models.

Conclusions : CysLT1 and CysLT2 receptors are expressed in UM patient samples and cell lines and an association between high CysLT1 expression and clinical parameters was identified. In addition, targeting of CysLT1, but not CysLT2, in UM is effective both in vitro and in vivo. We are currently developing cell line and patient-derived xenograft models of UM.

This is a 2020 ARVO Annual Meeting abstract.

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