Open Research Europe (Nov 2023)

Ergolide mediates anti-cancer effects on metastatic uveal melanoma cells and modulates their cellular and extracellular vesicle proteomes [version 2; peer review: 2 approved]

  • Husvinee Sundaramurthi,
  • Kieran Wynne,
  • Valentina Tonelotto,
  • Eve O’Reilly,
  • Fiona O'Connell,
  • Csenger Kovácsházi,
  • Marcel Costa-Garcia,
  • Simone Marcone,
  • Agnes Kittel,
  • Eva Pallinger,
  • Alfonso Blanco,
  • Breandán N. Kennedy,
  • Jose Maria Piulats Rodriguez,
  • Szabolcs Hambalkó,
  • Jacintha O'Sullivan,
  • Péter Ferdinandy,
  • Lasse D. Jensen,
  • David Matallanas,
  • Zoltán Giricz

Journal volume & issue
Vol. 3

Abstract

Read online

Background Uveal melanoma is a poor prognosis cancer. Ergolide, a sesquiterpene lactone isolated from Inula Brittanica, exerts anti-cancer properties. The objective of this study was to 1) evaluate whether ergolide reduced metastatic uveal melanoma (MUM) cell survival/viability in vitro and in vivo; and 2) to understand the molecular mechanism of ergolide action. Methods Ergolide bioactivity was screened via long-term proliferation assay in UM/MUM cells and in zebrafish MUM xenograft models. Mass spectrometry profiled proteins modulated by ergolide within whole cell or extracellular vesicle (EVs) lysates of the OMM2.5 MUM cell line. Protein expression was analyzed by immunoblots and correlation analyses to UM patient survival used The Cancer Genome Atlas (TCGA) data. Results Ergolide treatment resulted in significant, dose-dependent reductions (48.5 to 99.9%; p1.2). Immunoblotting of heme oxygenase 1 (HMOX1) and growth/differentiation factor 15 (GDF15) corroborated the proteomic data. Additional proteomics of EVs isolated from OMM2.5 cells treated with ergolide, detected 2931 proteins. There was a large overlap with EV proteins annotated within the Vesiclepedia compendium. Within the differentially expressed proteins, the proteasomal pathway was primarily altered. Interestingly, BRCA2 and CDKN1A Interacting Protein (BCCIP) and Chitinase Domain Containing 1 (CHID1), were the only proteins significantly differentially expressed by ergolide in both the OMM2.5 cellular and EV isolates and they displayed inverse differential expression in the cells versus the EVs. Conclusions Ergolide is a novel, promising anti-proliferative agent for UM/MUM. Proteomic profiling of OMM2.5 cellular/EV lysates identified candidate pathways elucidating the action of ergolide and putative biomarkers of UM, that require further examination.

Keywords