Antagonists of growth hormone-releasing hormone receptor induce apoptosis specifically in retinoblastoma cells

Wai Kit Chu, Ka Sin Law, Sun On Chan, Jason Cheuk Sing Yam, Li Jia Chen, Hao Zhang, Herman S Cheung, Norman L Block, Andrew V Schally, Chi Pui Pang

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

Retinoblastoma (RB) is the most common intraocular cancer in children worldwide. Current treatments mainly involve combinations of chemotherapies, cryotherapies, and laser-based therapies. Severe or late-stage disease may require enucleation or lead to fatality. Recently, RB has been shown to arise from cone precursor cells, which have high MDM2 levels to suppress p53-mediated apoptosis. This finding leads to the hypothesis that restoring apoptosis mechanisms in RBs could specifically kill the cancer cells without affecting other retinal cells. We have previously reported involvement of an extrapituitary signaling pathway of the growth hormone-releasing hormone (GHRH) in the retina. Here we show that the GHRH receptor (GHRH-R) is highly expressed in RB cells but not in other retinal cells. We induced specific apoptosis with two different GHRH-R antagonists, MIA-602 and MIA-690. Importantly, these GHRH-R antagonists do not trigger apoptosis in other retinal cells such as retinal pigmented epithelial cells. We delineated the gene expression profiles regulated by GHRH-R antagonists and found that cell proliferation genes and apoptotic genes are down- and up-regulated, respectively. Our results reveal the involvement of GHRH-R in survival and proliferation of RB and demonstrate that GHRH-R antagonists can specifically kill the RB cells.

Original languageEnglish (US)
Pages (from-to)14396-14401
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number50
DOIs
StatePublished - Dec 13 2016

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Keywords

  • Apoptosis
  • GHRH pathway
  • GHRH-R antagonist
  • Growth hormone-releasing hormone
  • Retinoblastoma

ASJC Scopus subject areas

  • General

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