Targeting Notch signaling as a novel therapy for retinoblastoma
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Laura Asnaghi1, Arushi Tripathy1, Qian Yang2, Harpreet Kaur1, Allison Hanaford1, Wayne Yu4, Charles G. Eberhart1,2,3
1Department of Pathology, Johns Hopkins University, School of Medicine, Baltimore, MD, USA
2Department of Ophthalmology, Johns Hopkins University, School of Medicine, Baltimore, MD, USA
3Department of Oncology, Johns Hopkins University, School of Medicine, Baltimore, MD, USA
4Microarray Core Facility, Sidney Kimmel Cancer Center, Johns Hopkins University, School of Medicine, Baltimore, MD, USA
Laura Asnaghi, email: [email protected]
Keywords: Notch, retinoblastoma, proliferation, melphalan, γ-secretase inhibitors
Received: April 30, 2016 Accepted: September 14, 2016 Published: September 20, 2016
Retinoblastoma is the most common intraocular malignancy of childhood. Notch plays a key role in retinal cells from which retinoblastomas arise, and we therefore studied the role of Notch signaling in promoting retinoblastoma proliferation. Moderate or strong nuclear expression of Hes1 was found in 10 of 11 human retinoblastoma samples analyzed immunohistochemically, supporting a role for Notch in retinoblastoma growth. Notch pathway components were present in WERI Rb1 and Y79 retinoblastoma lines, with Jag2 and DLL4 more highly expressed than other ligands, and Notch1 and Notch2 more abundant than Notch3. The cleaved/active form of Notch1 was detectable in both lines. Inhibition of the pathway, achieved using a γ-secretase inhibitor (GSI) or by downregulating Jag2, DLL4 or CBF1 using short hairpin RNA, potently reduced growth, proliferation and clonogenicity in both lines. Upregulation of CXCR4 and CXCR7 and downregulation of PI3KC2β were identified by microarray upon Jag2 suppression. The functional importance of PI3KC2β was confirmed using shRNA. Synergy was found by combining GSI with Melphalan at their IC50. These findings indicate that Notch pathway is active in WERI Rb1 and Y79, and in most human retinoblastoma samples, and suggest that Notch antagonists may represent a new approach to more effectively treat retinoblastoma.
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