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

Po Chun Tseng, Chia Ling Chen, Yan Shen Shan, Wen Teng Chang, Hsiao Sheng Liu, Tse Ming Hong, Chia Yuan Hsieh, Sheng Hsiang Lin, Chiou Feng Lin

研究成果: Article

7 引文 斯高帕斯(Scopus)

摘要

Background: Increased 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. Results: Inhibiting 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 κBa/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. Conclusion: An increase in ILK non-canonically promotes ERK1/2/NF-κB activation and leads to the growth of gastric cancer cells.

原文English
文章編號69
期刊Cell Communication and Signaling
12
發行號1
DOIs
出版狀態Published - 2014 一月 1

    指紋

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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