The CXCR4 antagonist R54 targets epithelial-mesenchymal transition (EMT) in human ovarian cancer cells

PLoS One. 2024 Dec 19;19(12):e0314735. doi: 10.1371/journal.pone.0314735. eCollection 2024.

Abstract

The axis CXCL12-CXCR4 is highly expressed in ovarian cancer where contributes to disease progression. Aim of the work was to evaluate the effect of the newly developed CXCR4 antagonist R54 on human ovarian cancer cells aggressiveness. CXCL12-CXCR4 axis was evaluated in human ovarian cancer cells through proliferation, migration and signaling CXCL12-dependents. Epithelial to mesenchymal transition (EMT) was analyzed through E-CADHERIN, N-CADHERIN, VIMENTIN, SNAIL1 and ΒETA-CATENIN by qRT-PCR, immunofluorescence and immunoblotting. R54 inhibited ovarian cancer cells proliferation and migration CXCL12-induced. Moreover, R54 inhibited CXCL12 dependent pERK1/2 and pAKT and reversed the CXCL12 induced EMT in ovarian cancer cells. Targeting CXCR4 with the new antagonist R54 consistently reverted the mesenchymal transition in human ovarian cancer cells reducing migratory and chemoresistance features.

MeSH terms

  • Cadherins / metabolism
  • Cell Line, Tumor
  • Cell Movement* / drug effects
  • Cell Proliferation* / drug effects
  • Chemokine CXCL12* / metabolism
  • Epithelial-Mesenchymal Transition* / drug effects
  • Female
  • Humans
  • Ovarian Neoplasms* / drug therapy
  • Ovarian Neoplasms* / metabolism
  • Ovarian Neoplasms* / pathology
  • Receptors, CXCR4* / antagonists & inhibitors
  • Receptors, CXCR4* / metabolism
  • Signal Transduction / drug effects
  • Vimentin / metabolism

Substances

  • Receptors, CXCR4
  • Chemokine CXCL12
  • CXCR4 protein, human
  • Vimentin
  • Cadherins

Grants and funding

The following funders supported this work: -Fondazione Italiana per la Ricerca sul Cancro (AIRC-IG24746 to SS) https://www.airc.it/fondazione/chi-siamo#:~:text=La%20Fondazione%20Italiana%20per%20la%20Ricerca%20sul%20Cancro%20%2D%20AIRC -Fondazione Italiana per la Ricerca sul Cancro (AIRC-IG18921 and IG25932 to SP) https://www.airc.it/fondazione/chi-siamo#:~:text=La%20Fondazione%20Italiana%20per%20la%20Ricerca%20sul%20Cancro%20%2D%20AIRC - Ministry of Health (RF-2016–02363995 and CO-2018–12367051 to SP) https://www.salute.gov.it/portale/home.html - Ministry of Health (Ricerca Corrente 2023 L3/13 to SP) https://www.salute.gov.it/portale/home.html - Ministry of Health (Ricerca Corrente 2023 L1/8 to LP) https://www.salute.gov.it/portale/home.html - NAN4TUM (Euronanomed 2019-044 to SS) https://euronanomed.net/funded-projects?calls=10th-joint-call-2019&coordinators=&countries= These funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.