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

Research output: Contribution to journalArticle

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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 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.

Original languageEnglish
Article number69
JournalCell Communication and Signaling
Volume12
Issue number1
DOIs
Publication statusPublished - 2014 Jan 1

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Stomach Neoplasms
Cells
Growth
Cell growth
Chemical activation
Cell Movement
Phosphatidylinositol 3-Kinases
integrin-linked kinase
HSC70 Heat-Shock Proteins
Ubiquitin-Protein Ligases
Ubiquitination
Cell adhesion
Proteasome Endopeptidase Complex
Epidermal Growth Factor
Cell Adhesion
Fluorouracil
Antineoplastic Agents
Small Interfering RNA
Cisplatin
Carcinogenesis

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

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title = "An increase in integrin-linked kinase noncanonically confers NF-κB-mediated growth advantages to gastric cancer cells by activating ERK1/2",
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 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.",
author = "Tseng, {Po Chun} and Chen, {Chia Ling} and Yan-Shen Shan and Chang, {Wen Teng} and Hsiao-Sheng Liu and Tse-Ming Hong and Hsieh, {Chia Yuan} and Sheng-Hsiang Lin and Lin, {Chiou Feng}",
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An increase in integrin-linked kinase noncanonically confers NF-κB-mediated growth advantages to gastric cancer cells by activating ERK1/2. / Tseng, Po Chun; Chen, Chia Ling; Shan, Yan-Shen; Chang, Wen Teng; Liu, Hsiao-Sheng; Hong, Tse-Ming; Hsieh, Chia Yuan; Lin, Sheng-Hsiang; Lin, Chiou Feng.

In: Cell Communication and Signaling, Vol. 12, No. 1, 69, 01.01.2014.

Research output: Contribution to journalArticle

TY - JOUR

T1 - An increase in integrin-linked kinase noncanonically confers NF-κB-mediated growth advantages to gastric cancer cells by activating ERK1/2

AU - Tseng, Po Chun

AU - Chen, Chia Ling

AU - Shan, Yan-Shen

AU - Chang, Wen Teng

AU - Liu, Hsiao-Sheng

AU - Hong, Tse-Ming

AU - Hsieh, Chia Yuan

AU - Lin, Sheng-Hsiang

AU - Lin, Chiou Feng

PY - 2014/1/1

Y1 - 2014/1/1

N2 - 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.

AB - 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.

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U2 - 10.1186/s12964-014-0069-3

DO - 10.1186/s12964-014-0069-3

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