C1q-tumour necrosis factor-related protein 8 (CTRP8) is a novel interaction partner of relaxin receptor RXFP1 in human brain cancer cells

Aleksandra Glogowska, Usakorn Kunanuvat, Jörg Stetefeld, Trushar R. Patel, Thatchawan Thanasupawat, Jerry Krcek, Ekkehard Weber, G. William Wong, Marc R. Del Bigio, Cuong Hoang-Vu, Sabine Hombach-Klonisch, Thomas Klonisch

Research output: Contribution to journalArticle

Abstract

We report a novel ligand-receptor system composed of the leucine-rich G-protein-coupled relaxin receptor, RXFP1, and the C1q-tumour necrosis factor-related protein 8 (CTRP8) in human primary brain cancer, a tumour entity devoid of the classical RXFP1 ligands, RLN1-3. In structural homology studies and computational docking experiments we delineated the N-terminal region of the globular C1q region of CTRP8 and the leucine-rich repeat units 7 and 8 of RXFP1 to mediate this new ligand-receptor interaction. CTRP8 secreted from HEK293T cells, recombinant human (rh) CTRP8, and short synthetic peptides derived from the C1q globular domain of human CTRP8 caused the activation of RXFP1 as determined by elevated intracellular cAMP levels and the induction of a marked pro-migratory phenotype in established glioblastoma (GB) cell lines and primary cells from GB patients. Employing a small competitor peptide, we were able to disrupt the CTRP8-RXFP1-induced increased GB motility. The CTRP8-RXFP1-mediated migration in GB cells involves the activation of PI3K and specific protein kinase C pathways and the increased production/secretion of the potent lysosomal protease cathepsin B (cathB), a known prognostic marker of GB. Specific inhibition of CTRP8-induced cathB activity effectively blocked the ability of primary GB to invade laminin matrices. Finally, co-immunoprecipitation studies revealed the direct interaction of human CTRP8 with RXFP1. Our results support a therapeutic approach in GB aimed at targeting multiple steps of the CTRP8-RXFP1 signalling pathway by a combined inhibitor and peptide-based strategy to block GB dissemination within the brain.

Original languageEnglish (US)
Pages (from-to)466-479
Number of pages14
JournalJournal of Pathology
Volume231
Issue number4
DOIs
StatePublished - Dec 2013

Keywords

  • CTRP8
  • RXFP1
  • brain cancer
  • cathepsin
  • relaxin receptor

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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  • Cite this

    Glogowska, A., Kunanuvat, U., Stetefeld, J., Patel, T. R., Thanasupawat, T., Krcek, J., Weber, E., Wong, G. W., Del Bigio, M. R., Hoang-Vu, C., Hombach-Klonisch, S., & Klonisch, T. (2013). C1q-tumour necrosis factor-related protein 8 (CTRP8) is a novel interaction partner of relaxin receptor RXFP1 in human brain cancer cells. Journal of Pathology, 231(4), 466-479. https://doi.org/10.1002/path.4257