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

Research output: Contribution to journalArticle

7 Citations (Scopus)

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

Fingerprint

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

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

Cite this

An increase in integrin-linked kinase non-canonically confers NF-κB-mediated growth advantages to gastric cancer cells by activating ERK1/2. / Tseng, P.-C.; Chen, C.-L.; Shan, Y.-S.; Chang, W.-T.; Liu, H.-S.; Hong, T.-M.; Hsieh, C.-Y.; Lin, S.-H.; Lin, C.-F.

In: Cell Communication and Signaling, Vol. 12, 2014, p. 69.

Research output: Contribution to journalArticle

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title = "An increase in integrin-linked kinase non-canonically 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 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.",
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",
author = "P.-C. Tseng and C.-L. Chen and Y.-S. Shan and W.-T. Chang and H.-S. Liu and T.-M. Hong and C.-Y. Hsieh and S.-H. Lin and C.-F. Lin",
note = "Export Date: 22 August 2016 Chemicals/CAS: mitogen activated protein kinase 1, 137632-08-7; mitogen activated protein kinase 3, 137632-07-6; phosphatidylinositol 3 kinase, 115926-52-8; phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase, 210488-47-4; protein serine threonine kinase; integrin-linked kinase; IQ motif containing GTPase activating protein 1; 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",
year = "2014",
doi = "10.1186/s12964-014-0069-3",
language = "English",
volume = "12",
pages = "69",
journal = "Cell Communication and Signaling",
issn = "1478-811X",
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TY - JOUR

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

AU - Tseng, P.-C.

AU - Chen, C.-L.

AU - Shan, Y.-S.

AU - Chang, W.-T.

AU - Liu, H.-S.

AU - Hong, T.-M.

AU - Hsieh, C.-Y.

AU - Lin, S.-H.

AU - Lin, C.-F.

N1 - Export Date: 22 August 2016 Chemicals/CAS: mitogen activated protein kinase 1, 137632-08-7; mitogen activated protein kinase 3, 137632-07-6; phosphatidylinositol 3 kinase, 115926-52-8; phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase, 210488-47-4; protein serine threonine kinase; integrin-linked kinase; IQ motif containing GTPase activating protein 1; 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

PY - 2014

Y1 - 2014

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 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.

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 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.

KW - guanosine triphosphatase activating protein

KW - immunoglobulin enhancer binding protein

KW - integrin-linked kinase

KW - IQ motif containing guanosine triphosphatase activating protein 1

KW - mitogen activated protein kinase 1

KW - mitogen activated protein kinase 3

KW - phosphatidylinositol 3 kinase

KW - phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase

KW - protein serine threonine kinase

KW - Ras protein

KW - animal

KW - apoptosis

KW - Bagg albino mouse

KW - cell motion

KW - cell proliferation

KW - cell survival

KW - human

KW - male

KW - metabolism

KW - stomach tumor

KW - tumor cell line

KW - wound healing

KW - Animals

KW - Apoptosis

KW - Cell Line, Tumor

KW - Cell Movement

KW - Cell Proliferation

KW - Cell Survival

KW - Humans

KW - Male

KW - Mice, Inbred BALB C

KW - Mitogen-Activated Protein Kinase 1

KW - Mitogen-Activated Protein Kinase 3

KW - NF-kappa B

KW - Phosphatidylinositol 3-Kinases

KW - Protein-Serine-Threonine Kinases

KW - PTEN Phosphohydrolase

KW - ras GTPase-Activating Proteins

KW - ras Proteins

KW - Stomach Neoplasms

KW - Wound Healing

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VL - 12

SP - 69

JO - Cell Communication and Signaling

JF - Cell Communication and Signaling

SN - 1478-811X

ER -