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


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
Issue number2
Early online dateFeb 10 2023
StatePublished - Feb 28 2023


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

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)


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