Inhibitor of differentiation or
DNA binding (Id-1) is a helix-loop-helix
protein that is over-expressed in many types of
cancer including
esophageal cancer. This study aims to investigate its effects on the phosphatidylinositol-3-kinase (PI3K)/Akt/
nuclear factor kappa B (NFkappaB) signaling pathway and the significance in protecting
esophageal cancer cells against apoptosis. We found elevated expression of phosphorylated forms of Akt,
glycogen synthase kinase 3beta and inhibitor of kappa B, as well as increased nuclear translocation of NFkappaB subunit p65 and NFkappaB
DNA-binding activity, in
esophageal cancer cells with stable ectopic Id-1 expression. Transient transfection of Id-1 into HEK293 cells confirmed activation of PI3K/Akt/NFkappaB signaling and the effects were counteracted by the PI3K inhibitor
LY294002. Treatment with
tumor necrosis factor-alpha (
TNF-alpha) elicited a significantly weaker apoptotic response, following a marked and sustained activation of Akt and NFkappaB in the Id-1-over-expressing cells, compared with the vector control. The effects of Id-1 on the PI3K/Akt/NFkappaB signaling pathway and apoptosis were reversed in
esophageal cancer cells transfected with
siRNA against Id-1. In addition, inhibition of PI3K or NFkappaB signaling using the PI3K inhibitor
LY294002 or the NFkappaB inhibitor
Bay11-7082 increased the sensitivity of Id-1-over-expressing
esophageal cancer cells to
TNF-alpha-induced apoptosis. Our results provide the first evidence that Id-1 induces the activation of PI3K/Akt/NFkappaB signaling pathway, and protects
esophageal cancer cells from
TNF-alpha-induced apoptosis in vitro. Inactivation of Id-1 may provide us with a novel strategy to improve the treatment and survival of patients with
esophageal cancer.