Nitric oxide suppression by secreted frizzled-related protein 2 drives retinoblastoma

Panneerselvam Jayabal, Fuchun Zhou, Xiuye Ma, Kathryn M. Bondra, Barron Blackman, Susan T. Weintraub, Yidong Chen, Patricia Chévez-Barrios, Peter J. Houghton, Brenda Gallie, Yuzuru Shiio

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Retinoblastoma is a cancer of the infant retina primarily driven by loss of the Rb tumor suppressor gene, which is undruggable. Here, we report an autocrine signaling, mediated by secreted frizzled-related protein 2 (SFRP2), which suppresses nitric oxide and enables retinoblastoma growth. We show that coxsackievirus and adenovirus receptor (CXADR) is the cell-surface receptor for SFRP2 in retinoblastoma cells; that CXADR functions as a “dependence receptor,” transmitting a growth-inhibitory signal in the absence of SFRP2; and that the balance between SFRP2 and CXADR determines nitric oxide production. Accordingly, high SFRP2 RNA expression correlates with high-risk histopathologic features in retinoblastoma. Targeting SFRP2 signaling by SFRP2-binding peptides or by a pharmacological inhibitor rapidly induces nitric oxide and profoundly inhibits retinoblastoma growth in orthotopic xenograft models. These results reveal a cytokine signaling pathway that regulates nitric oxide production and retinoblastoma cell proliferation and is amenable to therapeutic intervention.

Original languageEnglish (US)
Article number112103
JournalCell Reports
Volume42
Issue number2
DOIs
StatePublished - Feb 28 2023

Keywords

  • CP: Cancer
  • CXADR
  • SFRP2
  • cell-surface proteome
  • nitric oxide
  • proteomics
  • retinoblastoma
  • secretome
  • signaling

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology

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