Growth hormone-releasing hormone receptor antagonists inhibit human gastric cancer through downregulation of PAK1-STAT3/NF-κB signaling

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

Research output: Contribution to journalArticle

21 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)14745-14750
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number51
DOIs
StatePublished - Dec 20 2016

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p21-Activated Kinases
Hormone Antagonists
STAT3 Transcription Factor
Growth Hormone-Releasing Hormone
Stomach Neoplasms
Down-Regulation
Neoplasms
Therapeutics
somatotropin releasing hormone receptor
Cell Line
Survival Analysis
Nude Mice
Cultured Cells

Keywords

  • GHRH receptor
  • GHRH-R antagonist
  • PAK1
  • Prognostic predictor
  • Stomach cancer

ASJC Scopus subject areas

  • General

Cite this

Growth hormone-releasing hormone receptor antagonists inhibit human gastric cancer through downregulation of PAK1-STAT3/NF-κB signaling. / Gan, Jinfeng; Ke, Xiurong; Jiang, Jiali; Dong, Hongmei; Yao, Zhimeng; Lin, Yusheng; Lin, Wan; Wu, Xiao; Yan, Shumei; Zhuang, Yixuan; Chu, Wai Kit; Cai, Renzhi; Zhang, Xianyang; Cheung, Herman S; Block, Norman L; Pang, Chi Pui; Schally, Andrew V; Zhang, Hao.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 113, No. 51, 20.12.2016, p. 14745-14750.

Research output: Contribution to journalArticle

Gan, J, Ke, X, Jiang, J, Dong, H, Yao, Z, Lin, Y, Lin, W, Wu, X, Yan, S, Zhuang, Y, Chu, WK, Cai, R, Zhang, X, Cheung, HS, Block, NL, Pang, CP, Schally, AV & Zhang, H 2016, 'Growth hormone-releasing hormone receptor antagonists inhibit human gastric cancer through downregulation of PAK1-STAT3/NF-κB signaling', Proceedings of the National Academy of Sciences of the United States of America, vol. 113, no. 51, pp. 14745-14750. https://doi.org/10.1073/pnas.1618582114
Gan, Jinfeng ; Ke, Xiurong ; Jiang, Jiali ; Dong, Hongmei ; Yao, Zhimeng ; Lin, Yusheng ; Lin, Wan ; Wu, Xiao ; Yan, Shumei ; Zhuang, Yixuan ; Chu, Wai Kit ; Cai, Renzhi ; Zhang, Xianyang ; Cheung, Herman S ; Block, Norman L ; Pang, Chi Pui ; Schally, Andrew V ; Zhang, Hao. / Growth hormone-releasing hormone receptor antagonists inhibit human gastric cancer through downregulation of PAK1-STAT3/NF-κB signaling. In: Proceedings of the National Academy of Sciences of the United States of America. 2016 ; Vol. 113, No. 51. pp. 14745-14750.
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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.",
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AU - Gan, Jinfeng

AU - Ke, Xiurong

AU - Jiang, Jiali

AU - Dong, Hongmei

AU - Yao, Zhimeng

AU - Lin, Yusheng

AU - Lin, Wan

AU - Wu, Xiao

AU - Yan, Shumei

AU - Zhuang, Yixuan

AU - Chu, Wai Kit

AU - Cai, Renzhi

AU - Zhang, Xianyang

AU - Cheung, Herman S

AU - Block, Norman L

AU - Pang, Chi Pui

AU - Schally, Andrew V

AU - Zhang, Hao

PY - 2016/12/20

Y1 - 2016/12/20

N2 - 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.

AB - 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.

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KW - Prognostic predictor

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