title: Growth hormone-releasing hormone receptor antagonists inhibit human gastric cancer through downregulation of PAK1-STAT3/NF-κB signaling.
abstract: Gastric cancer (GC) ranks as the fourth most frequent in incidence and second in mortality among all cancers worldwide. The development of effective treatment approaches is an urgent requirement. Growth hormone-releasing hormone (GHRH) and GHRH receptor (GHRH-R) have been found to be present in a variety of tumoral tissues and cell lines. Therefore the inhibition of GHRH-R was proposed as a promising approach for the treatment of these cancers. However, little is known about GHRH-R and the relevant therapy in human GC. By survival analyses of multiple cohorts of GC patients, we identified that increased GHRH-R in tumor specimens correlates with poor survival and is an independent predictor of patient prognosis. We next showed that MIA-602, a highly potent GHRH-R antagonist, effectively inhibited GC growth in cultured cells. Further, this inhibitory effect was verified in multiple models of human GC cell lines xenografted into nude mice. Mechanistically, GHRH-R antagonists target GHRH-R and down-regulate the p21-activated kinase 1 (PAK1)-mediated signal transducer and activator of transcription 3 (STAT3)/nuclear factor-κB (NF-κB) inflammatory pathway. Overall, our studies establish GHRH-R as a potential molecular target in human GC and suggest treatment with GHRH-R antagonist as a promising therapeutic intervention for this cancer.
authors.affiliation: Cancer Research Center, Shantou University Medical College, Shantou 515041, China.
authors.forename: Jinfeng
authors.initials: J
authors.lastname: Gan
authors.affiliation: Cancer Research Center, Shantou University Medical College, Shantou 515041, China.
authors.forename: Xiurong
authors.initials: X
authors.lastname: Ke
authors.affiliation: Cancer Research Center, Shantou University Medical College, Shantou 515041, China.
authors.forename: Jiali
authors.initials: J
authors.lastname: Jiang
authors.affiliation: Cancer Research Center, Shantou University Medical College, Shantou 515041, China.
authors.forename: Hongmei
authors.initials: H
authors.lastname: Dong
authors.affiliation: Cancer Research Center, Shantou University Medical College, Shantou 515041, China.
authors.forename: Zhimeng
authors.initials: Z
authors.lastname: Yao
authors.affiliation: Cancer Research Center, Shantou University Medical College, Shantou 515041, China.
authors.forename: Yusheng
authors.initials: Y
authors.lastname: Lin
authors.affiliation: Cancer Research Center, Shantou University Medical College, Shantou 515041, China.
authors.forename: Wan
authors.initials: W
authors.lastname: Lin
authors.affiliation: Tumor Tissue Bank, Affiliated Cancer Hospital of Shantou University Medical College, Shantou 515041, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
authors.forename: Shumei
authors.initials: S
authors.lastname: Yan
authors.affiliation: Tumor Tissue Bank, Affiliated Cancer Hospital of Shantou University Medical College, Shantou 515041, China.
authors.forename: Yixuan
authors.initials: Y
authors.lastname: Zhuang
authors.affiliation: Department of Ophthalmology & Visual Sciences, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Wai Kit
authors.initials: WK
authors.lastname: Chu
authors.affiliation: Endocrine, Polypeptide, and Cancer Institute, Veterans Affairs Medical Center, Miami, FL 33125.|South Florida Veterans Affairs Foundation for Research and Education, Miami, FL 33125.|Division of Hematology and Oncology, Department of Medicine, Miller School of Medicine, University of Miami, Miami, FL 33136.|Division of Endocrinology, Department of Medicine, Miller School of Medicine, University of Miami, Miami, FL 33136.|Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136.
authors.forename: Renzhi
authors.initials: R
authors.lastname: Cai
authors.affiliation: Endocrine, Polypeptide, and Cancer Institute, Veterans Affairs Medical Center, Miami, FL 33125.|South Florida Veterans Affairs Foundation for Research and Education, Miami, FL 33125.|Division of Hematology and Oncology, Department of Medicine, Miller School of Medicine, University of Miami, Miami, FL 33136.|Division of Endocrinology, Department of Medicine, Miller School of Medicine, University of Miami, Miami, FL 33136.|Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136.
authors.forename: Xianyang
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Endocrine, Polypeptide, and Cancer Institute, Veterans Affairs Medical Center, Miami, FL 33125.|South Florida Veterans Affairs Foundation for Research and Education, Miami, FL 33125.|Department of Biomedical Engineering, University of Miami, Coral Gables, FL 33146.
authors.forename: Herman S
authors.initials: HS
authors.lastname: Cheung
authors.affiliation: Department of Pathology, Miller School of Medicine, University of Miami, Miami, FL 33136.
authors.forename: Norman L
authors.initials: NL
authors.lastname: Block
authors.affiliation: Department of Ophthalmology & Visual Sciences, The Chinese University of Hong Kong, Hong Kong, China.|Joint Shantou International Eye Center, Shantou University and The Chinese University of Hong Kong, Shantou 515041, China.
authors.forename: Chi Pui
authors.initials: CP
authors.lastname: Pang
authors.affiliation: Endocrine, Polypeptide, and Cancer Institute, Veterans Affairs Medical Center, Miami, FL 33125; haozhang@stu.edu.cn andrew.schally@va.gov.|South Florida Veterans Affairs Foundation for Research and Education, Miami, FL 33125.|Division of Hematology and Oncology, Department of Medicine, Miller School of Medicine, University of Miami, Miami, FL 33136.|Division of Endocrinology, Department of Medicine, Miller School of Medicine, University of Miami, Miami, FL 33136.|Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136.|Department of Pathology, Miller School of Medicine, University of Miami, Miami, FL 33136.
authors.forename: Andrew V
authors.initials: AV
authors.lastname: Schally
authors.affiliation: Cancer Research Center, Shantou University Medical College, Shantou 515041, China; haozhang@stu.edu.cn andrew.schally@va.gov.|Tumor Tissue Bank, Affiliated Cancer Hospital of Shantou University Medical College, Shantou 515041, China.|Department of Biotherapy, Affiliated Cancer Hospital of Shantou University Medical College, Shantou 515041, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Zhang
mesh_terms: D000368:Aged; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D018450:Disease Progression; D015536:Down-Regulation; D005260:Female; D006801:Humans; D007249:Inflammation; D053208:Kaplan-Meier Estimate; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism*; D011379:Prognosis; D018013:Receptors, Neuropeptide / Q000037:antagonists & inhibitors*; D018017:Receptors, Pituitary Hormone-Regulating Hormone / Q000037:antagonists & inhibitors*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D012680:Sensitivity and Specificity; D017337:Sermorelin / Q000031:analogs & derivatives / Q000737:chemistry; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays; D054462:p21-Activated Kinases / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; 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)-; D016328:NF-kappa B; D018013:Receptors, Neuropeptide; D018017:Receptors, Pituitary Hormone-Regulating Hormone; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D017337:Sermorelin; C515903:PAK1 protein, human; D054462:p21-Activated Kinases; C048250:somatotropin releasing hormone receptor
keywords: GHRH receptor; GHRH-R antagonist; PAK1; prognostic predictor; stomach cancer