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

P.-C. Tseng, C.-L. Chen, Y.-S. Shan, W.-T. Chang, H.-S. Liu, T.-M. Hong, C.-Y. Hsieh, S.-H. Lin, C.-F. Lin

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Abstract

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 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. CONCLUSION: An increase in ILK non-canonically promotes ERK1/2/NF-κB activation and leads to the growth of gastric cancer cells.
Original languageEnglish
Pages (from-to)69
Number of pages1
JournalCell Communication and Signaling
Volume12
DOIs
Publication statusPublished - 2014

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Keywords

  • guanosine triphosphatase activating protein
  • immunoglobulin enhancer binding protein
  • integrin-linked kinase
  • IQ motif containing guanosine triphosphatase activating protein 1
  • mitogen activated protein kinase 1
  • mitogen activated protein kinase 3
  • phosphatidylinositol 3 kinase
  • phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase
  • protein serine threonine kinase
  • Ras protein
  • animal
  • apoptosis
  • Bagg albino mouse
  • cell motion
  • cell proliferation
  • cell survival
  • human
  • male
  • metabolism
  • stomach tumor
  • tumor cell line
  • wound healing
  • Animals
  • Apoptosis
  • Cell Line, Tumor
  • Cell Movement
  • Cell Proliferation
  • Cell Survival
  • Humans
  • Male
  • Mice, Inbred BALB C
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • NF-kappa B
  • Phosphatidylinositol 3-Kinases
  • Protein-Serine-Threonine Kinases
  • PTEN Phosphohydrolase
  • ras GTPase-Activating Proteins
  • ras Proteins
  • Stomach Neoplasms
  • Wound Healing

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