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Discovery of BAR502, as potent steroidal antagonist of leukemia inhibitory factor receptor for the treatment of pancreatic adenocarcinoma

Frontiers in oncology, 2023-03, Vol.13, p.1140730-1140730 [Peer Reviewed Journal]

Copyright © 2023 Di Giorgio, Bellini, Lupia, Massa, Bordoni, Marchianò, Rosselli, Sepe, Rapacciuolo, Moraca, Morretta, Ricci, Urbani, Monti, Biagioli, Distrutti, Catalanotti, Zampella and Fiorucci. ;Copyright © 2023 Di Giorgio, Bellini, Lupia, Massa, Bordoni, Marchianò, Rosselli, Sepe, Rapacciuolo, Moraca, Morretta, Ricci, Urbani, Monti, Biagioli, Distrutti, Catalanotti, Zampella and Fiorucci 2023 Di Giorgio, Bellini, Lupia, Massa, Bordoni, Marchianò, Rosselli, Sepe, Rapacciuolo, Moraca, Morretta, Ricci, Urbani, Monti, Biagioli, Distrutti, Catalanotti, Zampella and Fiorucci ;ISSN: 2234-943X ;EISSN: 2234-943X ;DOI: 10.3389/fonc.2023.1140730 ;PMID: 36998446

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  • Title:
    Discovery of BAR502, as potent steroidal antagonist of leukemia inhibitory factor receptor for the treatment of pancreatic adenocarcinoma
  • Author: Di Giorgio, Cristina ; Bellini, Rachele ; Lupia, Antonio ; Massa, Carmen ; Bordoni, Martina ; Marchianò, Silvia ; Rosselli, Rosalinda ; Sepe, Valentina ; Rapacciuolo, Pasquale ; Moraca, Federica ; Morretta, Elva ; Ricci, Patrizia ; Urbani, Ginevra ; Monti, Maria Chiara ; Biagioli, Michele ; Distrutti, Eleonora ; Catalanotti, Bruno ; Zampella, Angela ; Fiorucci, Stefano
  • Subjects: bile acids ; LIF ; LIFR ; Oncology ; PDAC ; proliferation ; steroid
  • Is Part Of: Frontiers in oncology, 2023-03, Vol.13, p.1140730-1140730
  • Description: The leukemia inhibitory factor (LIF), is a cytokine belonging to IL-6 family, whose overexpression correlate with poor prognosis in cancer patients, including pancreatic ductal adenocarcinoma (PDAC). LIF signaling is mediate by its binding to the heterodimeric LIF receptor (LIFR) complex formed by the LIFR receptor and Gp130, leading to JAK1/STAT3 activation. Bile acids are steroid that modulates the expression/activity of membrane and nuclear receptors, including the Farnesoid-X-Receptor (FXR) and G Protein Bile Acid Activated Receptor (GPBAR1). Herein we have investigated whether ligands to FXR and GPBAR1 modulate LIF/LIFR pathway in PDAC cells and whether these receptors are expressed in human neoplastic tissues. The transcriptome analysis of a cohort of PDCA patients revealed that expression of LIF and LIFR is increased in the neoplastic tissue in comparison to paired non-neoplastic tissues. By assay we found that both primary and secondary bile acids exert a weak antagonistic effect on LIF/LIFR signaling. In contrast, BAR502 a non-bile acid steroidal dual FXR and GPBAR1 ligand, potently inhibits binding of LIF to LIFR with an IC of 3.8 µM. BAR502 reverses the pattern LIF-induced in a FXR and GPBAR1 independent manner, suggesting a potential role for BAR502 in the treatment of LIFR overexpressing-PDAC.
  • Publisher: Switzerland: Frontiers Media S.A
  • Language: English
  • Identifier: ISSN: 2234-943X
    EISSN: 2234-943X
    DOI: 10.3389/fonc.2023.1140730
    PMID: 36998446
  • Source: Open Access: DOAJ Directory of Open Access Journals
    Open Access: PubMed Central
    Geneva Foundation Free Medical Journals at publisher websites
    Alma/SFX Local Collection
    ROAD: Directory of Open Access Scholarly Resources
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