@article{36aba97bf2cf4a01af9b14877a6c7c47,
title = "Nitric oxide suppression by secreted frizzled-related protein 2 drives retinoblastoma",
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",
author = "Panneerselvam Jayabal and Fuchun Zhou and Xiuye Ma and Bondra, {Kathryn M.} and Barron Blackman and Weintraub, {Susan T.} and Yidong Chen and Patricia Ch{\'e}vez-Barrios and Houghton, {Peter J.} and Brenda Gallie and Yuzuru Shiio",
note = "Funding Information: We thank Robert Eisenman for helpful discussions and critical review of the manuscript. We thank Anna Falk for AF22 cells, the Cooperative Human Tissue Network for retinoblastoma tumor RNA samples, and the University of Texas Health Science Center at San Antonio (UTHSCSA) Institutional Mass Spectrometry Laboratory (Sammy Pardo and Dana Molleur) for mass spectrometry analysis. This work was supported by the National Cancer Institute , National Institutes of Health ( CA202485 to Y.S. and CA165995 to P.J.H.); by the Cancer Prevention and Research Institute of Texas ( RP160487 , RP160841 , and RP190385 to Y.S.; RP160716 to P.J.H.; RP160732 to Y.C.); by the Owens Medical Research Foundation (to Y.S.); by the National Center for Advancing Translational Sciences, National Institutes of Health , through the Clinical and Translational Science Award ( CTSA ) UL1 TR001120 ; by the Mays Cancer Center P30 Cancer Center Support Grant from the National Cancer Institute ( CA054174 ) for the mass spectrometry, flow cytometry, and next-generation sequencing shared resources; by the National Institutes of Health for purchase of the Orbitrap mass spectrometer ( 1S10RR025111-01 to S.T.W.) and the HiSeq 3000 sequencer ( 1S10OD021805-01 ); and by the Greehey Children{\textquoteright}s Cancer Research Institute Pilot Project Award (to Y.S.). Funding Information: We thank Robert Eisenman for helpful discussions and critical review of the manuscript. We thank Anna Falk for AF22 cells, the Cooperative Human Tissue Network for retinoblastoma tumor RNA samples, and the University of Texas Health Science Center at San Antonio (UTHSCSA) Institutional Mass Spectrometry Laboratory (Sammy Pardo and Dana Molleur) for mass spectrometry analysis. This work was supported by the National Cancer Institute, National Institutes of Health (CA202485 to Y.S. and CA165995 to P.J.H.); by the Cancer Prevention and Research Institute of Texas (RP160487, RP160841, and RP190385 to Y.S.; RP160716 to P.J.H.; RP160732 to Y.C.); by the Owens Medical Research Foundation (to Y.S.); by the National Center for Advancing Translational Sciences, National Institutes of Health, through the Clinical and Translational Science Award (CTSA) UL1 TR001120; by the Mays Cancer Center P30 Cancer Center Support Grant from the National Cancer Institute (CA054174) for the mass spectrometry, flow cytometry, and next-generation sequencing shared resources; by the National Institutes of Health for purchase of the Orbitrap mass spectrometer (1S10RR025111-01 to S.T.W.) and the HiSeq 3000 sequencer (1S10OD021805-01); and by the Greehey Children's Cancer Research Institute Pilot Project Award (to Y.S.). P.J. F.Z. and Y.S. designed the research. P.J. F.Z. X.M. K.M.B. B.B. S.T.W. Y.C. P.C.-B. P.J.H. and Y.S. performed the research. P.J. F.Z. K.M.B. B.B. S.T.W. Y.C. P.C.-B. P.J.H. and Y.S. analyzed the data. B.G. provided retinoblastoma cell lines and advice regarding the course of the project. Y.S. wrote the paper with input from other authors. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2023 The Author(s)",
year = "2023",
month = feb,
day = "28",
doi = "10.1016/j.celrep.2023.112103",
language = "English (US)",
volume = "42",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "2",
}