Cell Reports: Nitric Oxide Suppression by Secreted Frizzled-Related Protein 2 Drives Retinoblastoma (Shiio & Houghton Labs)

Panneerselvam Jayabal 1, Fuchun Zhou 1, Xiuye Ma 1, Kathryn M. Bondra 1, Barron Blackman 1, Susan T. Weintraub 2 3, Yidong Chen 1 3 4, Patricia Chévez-Barrios 5, Peter J. Houghton 1 3 6, Brenda Gallie 7, Yuzuru Shiio 1 2 3 8

Highlights

• The autocrine signaling mediated by SFRP2 drives retinoblastoma
• SFRP2 signaling suppresses NO production and maintains retinoblastoma growth
• CXADR serves as the receptor for SFRP2
• Targeting SFRP2 results in NO production and suppression of retinoblastoma growth

Summary

Retinoblastoma is a cancer of the infant retina primarily driven by the 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.

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