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 gp130757FF 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 gp130757FF 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.
Highlights
Of the seven Signal Transducer and Activator of Transcription (STAT) family members, Signal Transducer and Activator of Transcription-3 (STAT3) has been most consistently implicated in a range of common cancers in humans, including; lung, breast, ovarian, prostate, and colon [1,2,3,4]
For time-course studies, AGS cells were treated for 0–360 min with 5 mM WP1066 and phosphorylation of JAK2, STAT3, ERK1/2 and SHP-2 were analysed by Western blotting (Fig. 1B)
In this study we demonstrate that WP1066 dose-dependently inhibits the JAK2/STAT3 signaling pathway in human gastric cancer (AGS) cells, with a consequent 60% reduction in cell proliferation, and a smaller increase in apoptosis
Summary
Of the seven Signal Transducer and Activator of Transcription (STAT) family members, STAT3 has been most consistently implicated in a range of common cancers in humans, including; lung, breast, ovarian, prostate, and colon [1,2,3,4] This is true in human gastric cancer [5,6,7] in which STAT3 activation by chronic phosphorylation at tyrosine (Y) reside 705 has been linked to increased growth, angiogenesis, invasion and metastasis of the primary cancer [6,7,8]. IL-11/STAT3 has been shown to be an important driver of atrophic gastritis, the first precancerous lesion of the stomach following chronic infection by the bacterium Helicobacter pylori [14]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
