Carcinogenesis Advance Access published online on July 16, 2007
Carcinogenesis, doi:10.1093/carcin/bgm152
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Id-1 activation of PI3K/Akt/NF
B signaling pathway and its significance in promoting survival of esophageal cancer cells
Cancer Biology Group, Department of Anatomy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, 21 Sassoon Road, Pokfulam, Hong Kong, SAR, China
* Corresponding author: Dr. Annie L. M. Cheung, Department of Anatomy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, 21 Sassoon Road, Pokfulam, Hong Kong, SAR, China. Tel. No. (852) 28199293 Fax No. (852) 28170857, Email: lmcheung{at}hkucc.hku.hk
Id-1 (inhibitor of differentiation or DNA binding) is a helix-loop-helix protein that is overexpressed in many types of cancer including esophageal cancer. This study aims to investigate its effects on the PI3K/Akt/NF
B signaling pathway and the significance in protecting esophageal cancer cells against apoptosis. We found elevated expression of phosphorylated forms of Akt, GSK3ß and IB, as well as increased nuclear translocation of NFB subunit p65 and NFB 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/NFB signaling and the effects were counteracted by the PI3K inhibitor LY294002. Treatment with TNF-
elicited a significantly weaker apoptotic response, following a marked and sustained activation of Akt and NFB in the Id-1-overexpressing cells, compared with the vector control. The effects of Id-1 on the PI3K/Akt/NFB signaling pathway and apoptosis were reversed in esophageal cancer cells transfected with siRNA against Id-1. In addition, inhibition of PI3K or NFB signaling using the PI3K inhibitor LY294002 or the NFB inhibitor Bay11-7082 increased the sensitivity of Id-1-overexpressing esophageal cancer cells to TNF--induced apoptosis. Our results provide the first evidence that Id-1 induces the activation of PI3K/Akt/NFB signaling pathway, and protects esophageal cancer cells from TNF--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.
Received March 9, 2007; revised May 4, 2007; accepted June 22, 2007.
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