Document Detail


Muscarinic signaling in carcinoma cells.
MedLine Citation:
PMID:  12628476     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
We previously reported that activation of M(3) muscarinic acetylcholine receptors (mAChR) generates anti-proliferative signals and stimulates cadherin-mediated adhesion in the SCC-9 small cell lung carcinoma (SCLC) cell line. The current study was undertaken to determine the frequency of functional mAChR expression among different SCLC cell lines, and to test the ability of mAChR to generate anti-proliferative signals in different SCLC cell lines. The potential role of Rac1 in SCLC cell-cell adhesion was also investigated. Exposure to the mAChR agonist carbachol induces robust Ca(2+) mobilization (indicated by intracellular fluorescence of the Ca(2+)-binding dye Indo-1) in three SCLC cell lines (SCC-9, SCC-15, and NCI-H146), modest Ca(2+) mobilization in one SCLC cell line (NCI-H209), and no detectable Ca(2+) mobilization in two SCLC cell lines (SCC-18 and NCI-H82). The M(3) mAChR-selective antagonist 4-diphenylacetoxy-N-methylpiperidine methiodide inhibits Ca(2+) mobilization in all SCLC cell lines responding to carbachol. Incubation with carbachol for four hours significantly inhibits [3H]thymidine uptake in three of the four SCLC cell lines expressing functional mAChR (SCC-9, SCC-15, and NCI-H146 cells), but does not significantly alter [3H]thymidine uptake in the other SCLC cell lines examined. These results indicate that SCLC cell lines often express functional mAChR which elicit anti-proliferative signals when activated. To investigate the role of Rac1 in SCLC adhesion, SCC-9 cells were transiently transfected with cDNA constructs coding for Rac1, constitutively active Rac1(Val-12), or dominant negative Rac1(Asn-17) tagged to green fluorescent protein (GFP). SCC-9 cells expressing GFP-tagged constitutively active Rac1(Val-12) exhibit increased cell-cell adhesion in comparison to cells expressing GFP-Rac1 or GFP-Rac1(Asn-17). Constitutively active GFP-Rac1(Val-12), but not GFP-Rac1 or GFP-Rac1(Asn-17), accumulates at cell-cell junctions in SCC-9 cells. These results indicate that activated Rac1 increases SCLC cell-cell adhesion, consistent with the possibility that Rac1 activation contributes to increased SCLC cell-cell adhesion induced by mAChR stimulation. These findings indicate that activation of mAChR may play a significant role in regulating the proliferation and adhesion of SCLC cells. The demonstration by other investigators that acetylcholine is expressed by a variety of cells in the airways supports the possibility that acetylcholine may activate mAChR expressed by SCLC cells in primary tumors.
Authors:
Carol L Williams
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Life sciences     Volume:  72     ISSN:  0024-3205     ISO Abbreviation:  Life Sci.     Publication Date:  2003 Mar 
Date Detail:
Created Date:  2003-03-11     Completed Date:  2003-04-04     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  0375521     Medline TA:  Life Sci     Country:  England    
Other Details:
Languages:  eng     Pagination:  2173-82     Citation Subset:  IM    
Copyright Information:
Copyright 2003 Elsevier Science Inc.
Affiliation:
Molecular Pharmacology Laboratory, Guthrie Research Institute, One Guthrie Square, Sayre, PA 18840, USA. williams_carol@guthrie.org
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MeSH Terms
Descriptor/Qualifier:
Calcium / metabolism
Carcinoma, Small Cell / pathology*
Cell Adhesion
Cell Line
DNA, Complementary / metabolism
DNA, Neoplasm / biosynthesis,  genetics
Electroporation
Humans
Mutation / genetics
Receptors, Muscarinic / physiology*
Signal Transduction / physiology
Thymidine / metabolism
rac1 GTP-Binding Protein / physiology
Grant Support
ID/Acronym/Agency:
R01 HL63921/HL/NHLBI NIH HHS; R29 CA52471/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/DNA, Complementary; 0/DNA, Neoplasm; 0/Receptors, Muscarinic; 50-89-5/Thymidine; 7440-70-2/Calcium; EC 3.6.5.2/rac1 GTP-Binding Protein

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