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: Jinfeng Gan, Xiurong Ke, Jiali Jiang, Hongmei Dong, Zhimeng Yao, Yusheng Lin, Wan Lin, Xiao Wu, Shumei Yan, Yixuan Zhuang, Wai Kit Chu, Renzhi Cai, Xianyang Zhang, Herman S Cheung, Norman L Block, Chi Pui Pang, Andrew V Schally, Hao Zhang
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 113 Issue 51 Pg. 14745-14750 (12 20 2016) ISSN: 1091-6490 [Electronic] United States
• PMID: 27930339 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Antineoplastic Agents
• 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)-
• NF-kappa B
• Receptors, Neuropeptide
• Receptors, Pituitary Hormone-Regulating Hormone
• STAT3 Transcription Factor
• STAT3 protein, human
• Sermorelin
• PAK1 protein, human
• p21-Activated Kinases
• somatotropin releasing hormone receptor

Topics

• Aged
• Animals
• Antineoplastic Agents (pharmacology)
• Cell Line, Tumor
• Disease Progression
• Down-Regulation
• Female
• Humans
• Inflammation
• Kaplan-Meier Estimate
• Male
• Mice
• Mice, Nude
• Middle Aged
• NF-kappa B (metabolism)
• Prognosis
• Receptors, Neuropeptide (antagonists & inhibitors)
• Receptors, Pituitary Hormone-Regulating Hormone (antagonists & inhibitors)
• STAT3 Transcription Factor (metabolism)
• Sensitivity and Specificity
• Sermorelin (analogs & derivatives, chemistry)
• Signal Transduction
• Stomach Neoplasms (drug therapy, metabolism)
• Treatment Outcome
• Xenograft Model Antitumor Assays
• p21-Activated Kinases (metabolism)