title: Antagonists of growth hormone-releasing hormone receptor induce apoptosis specifically in retinoblastoma cells.
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.
authors.affiliation: Department of Ophthalmology & Visual Sciences, The Chinese University of Hong Kong, Hong Kong.
authors.forename: Wai Kit
authors.initials: WK
authors.lastname: Chu
authors.affiliation: Department of Ophthalmology & Visual Sciences, The Chinese University of Hong Kong, Hong Kong.
authors.forename: Ka Sin
authors.initials: KS
authors.lastname: Law
authors.affiliation: School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong.
authors.forename: Sun On
authors.initials: SO
authors.lastname: Chan
authors.affiliation: Department of Ophthalmology & Visual Sciences, The Chinese University of Hong Kong, Hong Kong.
authors.forename: Jason Cheuk Sing
authors.initials: JC
authors.lastname: Yam
authors.affiliation: Department of Ophthalmology & Visual Sciences, The Chinese University of Hong Kong, Hong Kong.
authors.forename: Li Jia
authors.initials: LJ
authors.lastname: Chen
authors.affiliation: Cancer Research Center, Shantou University Medical College, Shantou 515041, Guangdong, China.|Department of Biotherapy, Affiliated Cancer Hospital of Shantou University Medical College, Shantou 515041, China.|Tumor Tissue Bank, Affiliated Cancer Hospital of Shantou University Medical College, Shantou 515041, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Biomedical Engineering, University of Miami, Miami, FL 33146.
authors.forename: Herman S
authors.initials: HS
authors.lastname: Cheung
authors.affiliation: Department of Biomedical Engineering, University of Miami, Miami, FL 33146.|Department of Pathology, University of Miami Medical School, Miami, FL 33136.
authors.forename: Norman L
authors.initials: NL
authors.lastname: Block
authors.affiliation: Department of Pathology, University of Miami Medical School, Miami, FL 33136; andrew.schally@va.gov cppang@cuhk.edu.hk.|Veterans Affairs Medical Center, Miami, FL 33125.|Department of Medicine, Divisions of Hematology and Oncology and Endocrinology, University of Miami School of Medicine, Miami, FL 33136.|Sylvester Comprehensive Cancer Center, University of Miami School of Medicine, Miami, FL 33136.
authors.forename: Andrew V
authors.initials: AV
authors.lastname: Schally
authors.affiliation: Department of Ophthalmology & Visual Sciences, The Chinese University of Hong Kong, Hong Kong; andrew.schally@va.gov cppang@cuhk.edu.hk.
authors.forename: Chi Pui
authors.initials: CP
authors.lastname: Pang
mesh_terms: D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D006801:Humans; D018013:Receptors, Neuropeptide / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018017:Receptors, Pituitary Hormone-Regulating Hormone / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019572:Retinal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D012175:Retinoblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D017337:Sermorelin / Q000031:analogs & derivatives / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D059467:Transcriptome
chemical_list: C550121:GHRH(1-29)NH2, (PhAc-Ada)(0)-Tyr(1), Arg(2), Fpa(5,6), Ala(8), Har(9), Tyr(Me)(10), His(11), Orn(12,) Abu(15), His(20), Orn(21), Nle(27), Arg(28), Har(29)-; C000606673:N-Me-Tyr1,D-Ala2,Asn8,Arg29-NHCH3-JI-38; D018013:Receptors, Neuropeptide; D018017:Receptors, Pituitary Hormone-Regulating Hormone; D017337:Sermorelin; C048250:somatotropin releasing hormone receptor
keywords: GHRH pathway; GHRH-R antagonist; apoptosis; growth hormone-releasing hormone; retinoblastoma