Activation of matrix metalloproteinase-9 (MMP-9) by neurotensin promotes cell invasion and migration through ERK pathway in gastric cancer.
Neurotensin (NT) is distributed throughout the brain and gastrointestinal tract. Although the relationship between NT and matrix metalloproteinase-9 (MMP-9) activity in gastric cancer has not been reported, the elevation of MMP-9 and NT is reported in the breast, lung, prostate, and gastric cancer. The aim of our study is to investigate the relationship between NT and MMP-9 activity and the underlying signaling mechanism in gastric cancer cell lines. Commercial ELISA kits were used for estimation of NT and MMP-9 expression, and fluorescence resonance energy transfer (FRET) assay was used for measurement of MMP-9 activity. Cell migration and invasion were determined by wound healing and transwell assay. The expression of signaling proteins was measured by Western blotting. Our study reveals a positive correlation between increased plasma NT and MMP-9 activity in both of patient's serum and gastric cancer cell lines. A dose-dependent elevation of MMP-9 activity was observed by NT treatment in gastric cancer cells (MKN-1 and MKN-45) compared to untreated gastric cancer and normal epithelial cell (HFE-145). Moreover, NT-mediated migration and invasion were observed in gastric cancer cells unlike in normal cell. The signaling mechanism of NT in gastric cancer cells was confirmed in protein kinase C (PKC), extracellular-signal regulated kinase (ERK), and phosphatidylinositol 3-kinase (PI3K) pathway. In addition, pretreatment of gastric cancer cells with NTR1 inhibitor SR48692 was shown to significantly inhibit the NT-mediated MMP-9 activity, cell invasion, and migration. Our finding illustrated NTR1 could be a possible therapeutic target for gastric cancer.
Molecular Recognition Research Center, Korea Institute of Science and Technology, Hwarangno 14-gil 5, Seongbuk-ku, Seoul, 136-791, South Korea.
Hafeza
H
Akter
Min
M
Park
Oh-Seung
OS
Kwon
Eun Joo
EJ
Song
Won-Sang
WS
Park
Min-Jung
MJ
Kang
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D020935:MAP Kinase Signaling System / Q000235:genetics; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis* / Q000235:genetics; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000235:genetics; D009496:Neurotensin / Q000037:antagonists & inhibitors / Q000235:genetics*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D011720:Pyrazoles / Q000008:administration & dosage; D011804:Quinolines / Q000008:administration & dosage; D013274:Stomach Neoplasms / Q000235:genetics* / Q000473:pathology; D015533:Transcriptional Activation
D011720:Pyrazoles; D011804:Quinolines; C079087:SR 48692; D009496:Neurotensin; D019869:Phosphatidylinositol 3-Kinases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9