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Carcinogenesis Advance Access originally published online on July 16, 2007
Carcinogenesis 2007 28(11):2313-2320; doi:10.1093/carcin/bgm152
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Id-1 activation of PI3K/Akt/NF{kappa}B signaling pathway and its significance in promoting survival of esophageal cancer cells

Bin Li, Pak Yan Cheung, Xianghong Wang, Sai Wah Tsao, Ming Tat Ling, Yong Chuan Wong and Annie L.M. Cheung*

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

* To whom correspondence should be addressed. Tel: +852 28199293; Fax: +852 28170857; Email: lmcheung{at}hkucc.hku.hk

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 (NF{kappa}B) signaling pathway and the significance in protecting esophageal cancer cells against apoptosis. We found elevated expression of phosphorylated forms of Akt, glycogen synthase kinase 3ß and inhibitor of kappa B, as well as increased nuclear translocation of NF{kappa}B subunit p65 and NF{kappa}B 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/NF{kappa}B 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 NF{kappa}B in the Id-1-over-expressing cells, compared with the vector control. The effects of Id-1 on the PI3K/Akt/NF{kappa}B signaling pathway and apoptosis were reversed in esophageal cancer cells transfected with siRNA against Id-1. In addition, inhibition of PI3K or NF{kappa}B signaling using the PI3K inhibitor LY294002 or the NF{kappa}B 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/NF{kappa}B 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.

Abbreviations: Id-1, inhibitor of differentiation or DNA binding; PI3K, phosphatidylinositol-3-kinase; NF{kappa}B, nuclear factor kappa B; GSK3ß, glycogen synthase kinase 3ß; I{kappa}B, inhibitor of kappa B; ESCC, esophageal squamous cell carcinoma; MDM2, mouse double minute 2; mTOR, mammalian target of rapamycin; PARP, poly (ADP-ribose) polymerase; TUNEL, TdT-mediated dUTP nick-end labeling; TNF-{alpha}, tumor necrosis factor-{alpha}

Received March 9, 2007; revised May 4, 2007; accepted June 22, 2007.


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