title: Inhibition of the JAK2/STAT3 pathway reduces gastric cancer growth in vitro and in vivo.
abstract: Signal Transducer and Activator of Transcription-3 (STAT3) is constitutively activated in many cancers where it promotes growth, inflammation, angiogenesis and inhibits apoptosis. We have shown that STAT3 is constitutively activated in human gastric cancer, and that chronic IL-11-driven STAT3 transcriptional activity induces gastric tumourigenesis in the gp130(757FF) mouse model of gastric cancer development. Here we show that treatment of human AGS gastric cancer cells with the Janus Kinase (JAK) inhibitor WP1066 dose-, and time-dependently inhibits STAT3 phosphorylation, in conjunction with reduced JAK2 phosphorylation, reduced proliferation and increased apoptosis. In addition, application of intraperitoneal WP1066 for 2 weeks, reduced gastric tumour volume by 50% in the gp130(757FF) mouse coincident with reduced JAK2 and STAT3 activation compared with vehicle-treated, littermate controls. Gastric tumours from WP1066- treated mice had reduced polymorphonuclear inflammation, coincident with inhibition of numerous proinflammatory cytokines including IL-11, IL-6 and IL-1β, as well as the growth factors Reg1 and amphiregulin. These results show that WP1066 can block proliferation, reduce inflammation and induce apoptosis in gastric tumour cells by inhibiting STAT3 phosphorylation, and that many cytokines and growth factors that promote gastric tumour growth are regulated by STAT3-dependent mechanisms. WP1066 may form the basis for future therapeutics against gastric cancer.
authors.affiliation: Infection and Immunity Division, Murdoch Children's Research Institute, Parkville, Victoria, Australia.
authors.forename: Louise M
authors.initials: LM
authors.lastname: Judd
authors.affiliation: Infection and Immunity Division, Murdoch Children's Research Institute, Parkville, Victoria, Australia.
authors.forename: Treve R
authors.initials: TR
authors.lastname: Menheniott
authors.affiliation: Department of Pathology and Cancer Research Institute, University of South China, Hengyang, Hunan, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Ling
authors.affiliation: Infection and Immunity Division, Murdoch Children's Research Institute, Parkville, Victoria, Australia.
authors.forename: Cameron B
authors.initials: CB
authors.lastname: Jackson
authors.affiliation: Infection and Immunity Division, Murdoch Children's Research Institute, Parkville, Victoria, Australia.
authors.forename: Meegan
authors.initials: M
authors.lastname: Howlett
authors.affiliation: Infection and Immunity Division, Murdoch Children's Research Institute, Parkville, Victoria, Australia.
authors.forename: Anastasia
authors.initials: A
authors.lastname: Kalantzis
authors.affiliation: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Waldemar
authors.initials: W
authors.lastname: Priebe
authors.affiliation: Infection and Immunity Division, Murdoch Children's Research Institute, Parkville, Victoria, Australia.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Giraud
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D017370:Interleukin-11 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D053614:Janus Kinase 2 / Q000378:metabolism*; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D013274:Stomach Neoplasms / Q000378:metabolism* / Q000517:prevention & control*; D020032:Tyrphostins / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D017370:Interleukin-11; D015850:Interleukin-6; D011725:Pyridines; D050796:STAT3 Transcription Factor; D020032:Tyrphostins; C519885:WP1066; C507924:JAK2 protein, human; D053614:Janus Kinase 2