An increase in integrin-linked kinase non-canonically confers NF-κB-mediated growth advantages to gastric cancer cells by activating ERK1/2

Cell Communication and Signaling

Research

Chia-Ling Chen¹  Wen-Teng Chang²  Hsiao-Sheng Liu³  Tse-Ming Hong⁴  Chia-Yuan Hsieh⁴  Po-Chun Tseng⁴  Sheng-Hsiang Lin⁴  Chiou-Feng Lin⁵  Yan-Shen Shan⁶ 

[1] Center for Translational Medicine, Taipei Medical University, Taipei 110, Taiwan;Department of Biological Science and Technology, Chung Hwa University of Medical Technology, Tainan 717, Taiwan;Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan;Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan;Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan;Center of Infectious Disease and Signaling Research, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan;Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 110, Taiwan;Department of Microbiology and Immunology, College of Medicine, Taipei Medical University, Taipei 110, Taiwan;Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan;Department of Surgery, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan;

关键词: ILK;    Cell growth;    IQGAP1;    ERK1/2;    NK-κB;   

DOI  :  10.1186/s12964-014-0069-3

 received in 2014-05-07, accepted in 2014-10-19,  发布年份 2014

来源: Springer

【 摘 要 】

BackgroundIncreased activity or expression of integrin-linked kinase (ILK), which regulates cell adhesion, migration, and proliferation, leads to oncogenesis. We identified the molecular basis for the regulation of ILK and its alternative role in conferring ERK1/2/NF-κB-mediated growth advantages to gastric cancer cells.ResultsInhibiting ILK with short hairpin RNA or T315, a putative ILK inhibitor, abolished NF-κB-mediated the growth in the human gastric cancer cells AGS, SNU-1, MKN45, and GES-1. ILK stimulated Ras activity to activate the c-Raf/MEK1/2/ERK1/2/ribosomal S6 kinase/inhibitor of κBα/NF-κB signaling by facilitating the formation of the IQ motif-containing GTPase-activating protein 1 (IQGAP1)-Ras complex. Forced enzymatic ILK expression promoted cell growth by facilitating ERK1/2/NF-κB signaling. PI3K activation or decreased PTEN expression prolonged ERK1/2 activation by protecting ILK from proteasome-mediated degradation. C-terminus of heat shock cognate 70 interacting protein, an HSP90-associated E3 ubiquitin ligase, mediated ILK ubiquitination to control PI3K- and HSP90-regulated ILK stabilization and signaling. In addition to cell growth, the identified pathway promoted cell migration and reduced the sensitivity of gastric cancer cells to the anticancer agents 5-fluorouracil and cisplatin. Additionally, exogenous administration of EGF as well as overexpression of EGFR triggered ILK- and IQGAP1-regulated ERK1/2/NF-κB activation, cell growth, and migration.ConclusionAn increase in ILK non-canonically promotes ERK1/2/NF-κB activation and leads to the growth of gastric cancer cells.

【 授权许可】

Unknown   
© Tseng et al.; licensee BioMed Central Ltd. 2014. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.