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
N1 - Funding Information:
We thank the Immunobiology Core, Research Center of Clinical Medicine, National Cheng Kung University Hospital for providing services, including training, technical support, and assistance with the experimental design and data analysis using the Flow Cytometry Core facilities. This study was supported by grant NSC 100-2320-B-006-009-MY3 from the National Science Council, Taiwan.
Publisher Copyright:
© 2014 Tseng et al.; licensee BioMed Central Ltd.
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 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.
UR - http://www.scopus.com/inward/record.url?scp=84964695261&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84964695261&partnerID=8YFLogxK
U2 - 10.1186/s12964-014-0069-3
DO - 10.1186/s12964-014-0069-3
M3 - Article
C2 - 25398317
AN - SCOPUS:84964695261
VL - 12
JO - Cell Communication and Signaling
JF - Cell Communication and Signaling
SN - 1478-811X
IS - 1
M1 - 69
ER -