April 2014
Volume 55, Issue 13
ARVO Annual Meeting Abstract  |   April 2014
Pharmacologic Targeting of Skp2 in Retinoblastoma
Author Affiliations & Notes
  • Xiaoliang Leon Xu
    Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY
    Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, NY
  • Timothy Cardozo
    Department of Biochemistry and Molecular Pharmacology, New York University, New York, NY
  • Dan-Ning Hu
    New York Eye and Ear Infirmary, New York Medical College, New York, NY
  • David Cobrinik
    The Saban Research Institute, Children’s Hospital Los Angeles, University of South California, Los Angeles, NY
  • David H Abramson
    Ophthalmic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY
  • Suresh Jhanwar
    Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY
  • Footnotes
    Commercial Relationships Xiaoliang Xu, None; Timothy Cardozo, None; Dan-Ning Hu, None; David Cobrinik, None; David Abramson, None; Suresh Jhanwar, None
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science April 2014, Vol.55, 850. doi:
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      Xiaoliang Leon Xu, Timothy Cardozo, Dan-Ning Hu, David Cobrinik, David H Abramson, Suresh Jhanwar; Pharmacologic Targeting of Skp2 in Retinoblastoma. Invest. Ophthalmol. Vis. Sci. 2014;55(13):850.

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      © ARVO (1962-2015); The Authors (2016-present)

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Purpose: Retinoblastoma is the most common primary intraocular malignancy in children. Significant numbers of patients still lose their eyes and even their lives in developing countries, in spite of current advances in the treatment of retinoblastoma. Previously our studies showed that retinoblastomas exhibit retinal cone precursor properties and depend on cone-specific thyroid hormone receptor beta2 (TRB2) and SKP2 signaling (Xu et al, 2009; Wang et al, 2010). In this study, we sought to suppress retinoblastoma cell growth by chemical SKP2 inhibitors as a prelude to targeted therapy in vitro and in vivo.

Methods: We knocked down TRB2 and SKP2 or over-expressed p27 in retinoblastoma cells to investigate SKP2 and p27 signaling alterations. The retinoblastoma cell lines Y79, WERI, and RB177 were treated with SKP2 inhibitors C1, C2 (Wu et al, 2012), #25, and #25-9(Chan et al, 2013) at different concentrations, following which Western blotting was performed to study SKP2 and p27 expression as well as ubiquitination.

Results: TRB2 knockdown in Y79 and RB177 caused SKP2 downregulation and degradation, p27 up-regulation, and S phase arrest, whereas, SKP2 knockdown or p27 over-expression caused p27 accumulation and G1-S arrest. In the cell lines Y79, WERI, and RB177, treatment with C1 caused SKP2 ubiquitination and degradation, p27 de-ubiquitination and accumulation, and cell growth arrest. Compounds C2, #25, and #25-9, on the other hand exhibited only moderate effects on suppressing retinoblastoma growth without significant p27 level changes.

Conclusions: Retinoblastoma tumorigenesis depends on cone-specific TRB2 and SKP2 signaling. SKP2 is the synthetic lethal gene in retinoblastoma with RB1 loss. SKP2 inihibitor C1 significantly suppresses retinoblastoma cell growth by SKP2 degradation and p27 accumulation. In vivo animal model investigation of the effects of C1 on retinoblastoma cell growth is therefore warranted, and, in the long term, SKP2 targeted therapy, may be a promising therapeutic strategy for the treatment of retinoblastoma.

Keywords: 703 retinoblastoma • 744 tumors • 637 pathology: experimental  

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