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.