Mitogen-activated protein kinase (MAPK) pathways regulate multiple cellular functions and are highly active in many types of human
cancers.
Apoptosis signal-regulating kinase 1 (ASK1) is an upstream MAPK involved in apoptosis,
inflammation, and
carcinogenesis. This study investigated the role of ASK1 in the development of
gastric cancer. In human
gastric cancer specimens, we observed increased ASK1 expression, compared to nontumor epithelium. Using a chemically induced murine gastric
tumorigenesis model, we observed increased
tumor ASK1 expression, and ASK1 knockout mice had both fewer and smaller
tumors than wild-type (WT) mice. ASK1
siRNA inhibited cell proliferation through the accumulation of cells in G1 phase of the cell cycle, and reduced
cyclin D1 expression in
gastric cancer cells, whereas these effects were uncommon in other
cancer cells. ASK1 overexpression induced the transcription of
cyclin D1, through
AP-1 activation, and ASK1 levels were regulated by
cyclin D1, via the Rb-E2F pathway. Exogenous ASK1 induced
cyclin D1 expression, followed by elevated expression of endogenous ASK1. These results indicate an autoregulatory mechanism of ASK1 in the development of
gastric cancer. Targeting this positive feedback loop, ASK1 may present a potential therapeutic target for the treatment of advanced
gastric cancer.