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


CONCLUSIONS
An increase in ILK non-canonically promotes ERK1/2/NF-κB activation and leads to the growth of gastric cancer cells.
Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, 701, Taiwan. iluc0720@hotmail.com.
Po-Chun
PC
Tseng
Center for Translational Medicine, Taipei Medical University, Taipei, 110, Taiwan. chialing811@gmail.com.
Chia-Ling
CL
Chen
Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, 701, Taiwan. ysshan@mail.ncku.edu.tw.|Department of Surgery, College of Medicine, National Cheng Kung University, Tainan, 701, Taiwan. ysshan@mail.ncku.edu.tw.
Yan-Shen
YS
Shan
Department of Biological Science and Technology, Chung Hwa University of Medical Technology, Tainan, 717, Taiwan. bicowtc@gmail.com.
Wen-Teng
WT
Chang
Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, 701, Taiwan. a713@mail.ncku.edu.tw.
Hsiao-Sheng
HS
Liu
Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, 701, Taiwan. tmhong@mail.ncku.edu.tw.
Tse-Ming
TM
Hong
Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, 701, Taiwan. dyoushus@yahoo.com.tw.
Chia-Yuan
CY
Hsieh
Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, 701, Taiwan. shlin922@mail.ncku.edu.tw.
Sheng-Hsiang
SH
Lin
Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, 701, Taiwan. cflin2014@tmu.edu.tw.|Center of Infectious Disease and Signaling Research, College of Medicine, National Cheng Kung University, Tainan, 701, Taiwan. cflin2014@tmu.edu.tw.|Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, 110, Taiwan. cflin2014@tmu.edu.tw.|Department of Microbiology and Immunology, College of Medicine, Taipei Medical University, Taipei, 110, Taiwan. cflin2014@tmu.edu.tw.
Chiou-Feng
CF
Lin
D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D002470:Cell Survival; D006801:Humans; D008297:Male; D008807:Mice, Inbred BALB C; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D013274:Stomach Neoplasms / Q000378:metabolism*; D014945:Wound Healing; D020703:ras GTPase-Activating Proteins / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism; D000099200:Scaffold Protein ILK
D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D016328:NF-kappa B; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D020703:ras GTPase-Activating Proteins; D018631:ras Proteins; D000099200:Scaffold Protein ILK; C101203:IQ motif containing GTPase activating protein 1