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

Cell Rep. 2023 Feb 28;42(2):112103. doi: 10.1016/j.celrep.2023.112103. Epub 2023 Feb 13.

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.

Keywords: CP: Cancer; CXADR; SFRP2; cell-surface proteome; nitric oxide; proteomics; retinoblastoma; secretome; signaling.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Humans
  • Nitric Oxide
  • Retinal Neoplasms*
  • Retinoblastoma*
  • Secreted Frizzled-Related Proteins
  • Signal Transduction

Substances

  • Nitric Oxide
  • Secreted Frizzled-Related Proteins
  • SFRP2 protein, human