June 2023
Volume 64, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2023
Growth hormone-releasing hormone receptor (GHRH-R) antagonist MIA-602 suppresses retinoblastoma via downregulating MEK-ERK1/2 signaling
Author Affiliations & Notes
  • Linbin Zhou
    Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong, Hong Kong
  • Danny S.C. Ng
    Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong, Hong Kong
  • Jason C. Yam
    Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong, Hong Kong
    Hong Kong Hub of Paediatric Excellence, The Chinese University of Hong Kong, Hong Kong, Hong Kong
  • Li Jia Chen
    Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong, Hong Kong
    Hong Kong Hub of Paediatric Excellence, The Chinese University of Hong Kong, Hong Kong, Hong Kong
  • Clement C. Tham
    Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong, Hong Kong
    Hong Kong Hub of Paediatric Excellence, The Chinese University of Hong Kong, Hong Kong, Hong Kong
  • Calvin C P Pang
    Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong, Hong Kong
    Hong Kong Hub of Paediatric Excellence, The Chinese University of Hong Kong, Hong Kong, Hong Kong
  • WAI KIT CHU
    Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong, Hong Kong
    Hong Kong Hub of Paediatric Excellence, The Chinese University of Hong Kong, Hong Kong, Hong Kong
  • Footnotes
    Commercial Relationships   Linbin Zhou None; Danny S.C. Ng None; Jason C. Yam None; Li Jia Chen None; Clement Tham None; Calvin Pang None; WAI KIT CHU None
  • Footnotes
    Support  United College Early Career Research Excellence Award (2019 to W.K.C); General Research Fund, Research Grants Council, Hong Kong (14104621 and 14102522 to W.K.C.); The Chinese University of Hong Kong Direct Grant (2020.067 and 2021.046 to W.K.C).
Investigative Ophthalmology & Visual Science June 2023, Vol.64, 1318. doi:
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    • Get Citation

      Linbin Zhou, Danny S.C. Ng, Jason C. Yam, Li Jia Chen, Clement C. Tham, Calvin C P Pang, WAI KIT CHU; Growth hormone-releasing hormone receptor (GHRH-R) antagonist MIA-602 suppresses retinoblastoma via downregulating MEK-ERK1/2 signaling. Invest. Ophthalmol. Vis. Sci. 2023;64(8):1318.

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

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Abstract

Purpose : Retinoblastoma (RB) is the most common primary intraocular malignancy in childhood. Delay in treatment or resistance to chemotherapy results in enucleation or threatening the lives of RB patients. Growth hormone-releasing hormone receptor (GHRH-R) is highly expressed in RB cells. MIA-602, a GHRH-R antagonist, can specifically exert pro-apoptotic effects on RB cells in vitro, while in vivo anti-tumor effects of MIA-602 and the underlying mechanisms remain not fully understood. Hence, we aimed to investigate the in vivo anti-tumor effects of MIA-602 and the underlying mechanisms.

Methods : Propidium iodide (PI) staining was used to measure the proportion of sub-G1 population of RB cell lines Y79 and WERI-RB1 after MIA-602 or a selective ERK inhibitor treatment. Colony formation assay was used to detect the effects of MIA-602 or the ERK inhibitor on the stemness of RB cells. CCK8 assay was utilized to determine the effects of MIA-602 or the ERK inhibitor on the RB cell viability. Western blotting was used to measure MEK and ERK1/2 phosphorylation after MIA-602 treatment. An orthotopic cell line-derived xenograft (CDX) tumor model by subretinal injection of Y79 cells in athymic nude mice was established to test the anti-tumor effects of MIA-602 via TUNEL assay and immunostaining. Unpaired Student's t-test or one-way ANOVA test was used for data analysis.

Results : We found that MIA-602 substantially increased the proportion of sub-G1 population of Y79 and WERI-RB1 cells (p<0.05), indicating MIA-602-induced apoptosis. Moreover, MIA-602 significantly decreased the cell viability and colony formation of both cell lines in a dose-dependent manner (p<0.05). Notably, intravitreal injection of MIA-602 promoted RB tumor apoptosis and hindered tumor growth in the orthotopic CDX tumor model (p<0.05). Conversely, GHRH-R agonist MR-409 markedly increased the proliferation of both cell lines (p<0.05). Mechanistically, MIA-602 decreased the phosphorylation of ERK1/2 and its upstream regulator MEK in both cell lines and the CDX tumor model, while MR-409 enhanced MEK and ERK1/2 phosphorylation in both cell lines. A selective ERK1/2 inhibitor suppressed ERK1/2 phosphorylation and abolished the pro-proliferative effects induced by MR-409 in both cell lines (p<0.05).

Conclusions : GHRH-R antagonist MIA-602 promotes apoptosis of RB cells via downregulating MEK-ERK1/2 signaling.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.

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