Document Detail

Sodium hydrogen exchanger and phospholipase D are required for alpha1-adrenergic receptor stimulation of metalloproteinase-9 and cellular invasion in CCL39 fibroblasts.
MedLine Citation:
PMID:  18539131     Owner:  NLM     Status:  MEDLINE    
Matrix metalloproteinase 9 (MMP-9) plays a critical role in digesting the extracellular matrix and has a vital function in tumor metastasis and invasion; this protease activity is significantly increased in non-small cell lung cancers. The sodium hydrogen exchanger isoform 1 (NHE1) functions as a focal point for signal coordination and cytoskeletal reorganization. NHE1 is thought to play a central role in establishing signaling components at the leading edge of a migrating cell. Therefore, we studied the relationship between NHE1 and MMP-9 activity in Chinese hamster lung fibroblasts (CCL39) stimulated with phenylephrine (PE). We show that PE increases MMP-9 gelatinolytic activity in CCL39 cells. The inhibition of phospholipase D (PLD) signaling abrogated PE-induced MMP-9 activity. The role of PLD as an essential signaling intermediate was confirmed when the addition of permeable phosphatidic acid increased MMP-9 activity in the same cells. PE-induced invasion was increased 1.9-fold over controls and the PE response was lost when 1-butanol was used to block PLD signaling. Cells pre-treated with the NHE1 inhibitor, 5-(N-ethyl-N-isopropyl) amiloride (EIPA) prior to PE addition resulted in a notable decrease in MMP-9 activation and cell invasion as compared to untreated PE-stimulated cells. CCL39 NHE1 null cells demonstrated no increase in MMP-9 protease activity or cell invasion in response to PE treatment. Reconstitution of NHE1 expression recovered the PE-induced activation of protease activity and cell invasion. MMP-9 processing was altered in cells expressing a proton transport defective NHE1 but retained the ability to respond to PE. Conversely, cells expressing an ezrin, radixin, moesin (ERM)-binding deficient NHE1 had a lower MMP-9 activity and the protease did not respond to PE addition. Parallel studies on NCI-H358 non-small cell lung cancer (NSCL) cells showed that PE stimulated both MMP-9 activity and cell invasion in an NHE1 dependent manner. This work describes for the first time a PE-induced relationship between NHE1 and MMP-9 and a new potential mechanism by which NHE1 could promote tumor formation and metastasis.
Jennifer Taves; Danielle Rastedt; Jenny Canine; Dave Mork; Mark A Wallert; Joseph J Provost
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2008-05-27
Journal Detail:
Title:  Archives of biochemistry and biophysics     Volume:  477     ISSN:  1096-0384     ISO Abbreviation:  Arch. Biochem. Biophys.     Publication Date:  2008 Sep 
Date Detail:
Created Date:  2008-08-13     Completed Date:  2008-09-10     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0372430     Medline TA:  Arch Biochem Biophys     Country:  United States    
Other Details:
Languages:  eng     Pagination:  60-6     Citation Subset:  IM    
Departments of Chemistry and Biosciences, Minnesota State University Moorhead, Hagen Hall, Moorhead, MN 56563, USA.
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MeSH Terms
Adrenergic alpha-Agonists / pharmacology
Blotting, Western
Carcinoma, Non-Small-Cell Lung / enzymology,  pathology*
Cell Line
Cell Line, Tumor
Electrophoresis, Polyacrylamide Gel
Enzyme Activation
Fibroblasts / cytology,  drug effects,  enzymology,  metabolism
Glycerophospholipids / biosynthesis
Lung Neoplasms / enzymology,  pathology*
Matrix Metalloproteinase 9 / metabolism*
Neoplasm Invasiveness
Phenylephrine / pharmacology
Phospholipase D / antagonists & inhibitors,  metabolism*
Receptors, Adrenergic, alpha-1 / agonists,  physiology*
Sodium-Hydrogen Antiporter / metabolism*
Grant Support
1 R15 HL074924-01A1/HL/NHLBI NIH HHS; 5 R01 HL074924-URS/HL/NHLBI NIH HHS
Reg. No./Substance:
0/Adrenergic alpha-Agonists; 0/Glycerophospholipids; 0/Receptors, Adrenergic, alpha-1; 0/Sodium-Hydrogen Antiporter; 0/growth factor-activatable Na-H exchanger NHE-1; 0/phosphatidylbutanol; 59-42-7/Phenylephrine; EC D; EC Metalloproteinase 9

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