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

• Published in: Proceedings of the National Academy of Sciences - PNAS 2016-12, Vol.113 (50), p.14396-14401
• Main Authors: Chu, Wai Kit, Law, Ka Sin, Chan, Sun On, Yam, Jason Cheuk Sing, Chen, Li Jia, Zhang, Hao, Cheung, Herman S., Block, Norman L., Schally, Andrew V., Pang, Chi Pui
• Format: Article
• Language: English
• Subjects: Apoptosis; Apoptosis - drug effects; Apoptosis - genetics; Biological Sciences; Cancer; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Proliferation - genetics; Cell Survival - drug effects; Cell Survival - genetics; Chemotherapy; Children & youth; Gene expression; Hormones; Humans; Receptors, Neuropeptide - agonists; Receptors, Neuropeptide - antagonists & inhibitors; Receptors, Neuropeptide - metabolism; Receptors, Pituitary Hormone-Regulating Hormone - agonists; Receptors, Pituitary Hormone-Regulating Hormone - antagonists & inhibitors; Receptors, Pituitary Hormone-Regulating Hormone - metabolism; Retina; Retinal Neoplasms - drug therapy; Retinal Neoplasms - metabolism; Retinal Neoplasms - pathology; Retinoblastoma - drug therapy; Retinoblastoma - metabolism; Retinoblastoma - pathology; Sermorelin - analogs & derivatives; Sermorelin - pharmacology; Signal Transduction - drug effects; Transcriptome
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1617427113

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.