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Regulation of Integrin-Mediated Adhesion by Muscarinic Acetylcholine Receptors and Protein Kinase C in Small Cell Lung Carcinoma

Robert L. Quigley; Shulamith H. Shafer; Carol L. Williams
Author and Funding Information

Affiliations: From the Department of Cardiothoracic Surgery, Guthrie Research Institute, Sayre, Pa.,  From the Department of Guthrie Clinic, and the Molecular Pharmacology Laboratory, Guthrie Research Institute, Sayre, Pa.

Affiliations: From the Department of Cardiothoracic Surgery, Guthrie Research Institute, Sayre, Pa.,  From the Department of Guthrie Clinic, and the Molecular Pharmacology Laboratory, Guthrie Research Institute, Sayre, Pa.


1998 by the American College of Chest Physicians


Chest. 1998;114(3):839-846. doi:10.1378/chest.114.3.839
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Abstract

Study objectives: Improved understanding of the phenotypic characteristics of small cell lung cancer (SCLC) cells may facilitate the development of new therapies for this bronchogenic malignancy with early metastases. Herein we investigate whether activation of the M3 subtype of muscarinic acetylcholine receptor (mAChR) expressed on SCLC cells affects β1-integrin-mediated adhesion of these cells.

Design: Adhesion of the SCLC cell lines SCC-9 and NCI-H345 to extracellular matrix (ECM) proteins was investigated. Cell adhesion was quantified by labeling the cells with either toluidine blue dye and measuring optical density or 3H-thymidine and measuring β-activity. Fluorescence-activated cell sorting was used to quantify the SCLC cell surface expression of β1-integrins.

Setting: Experiments were conducted in the Molecular Pharmacology Laboratory, Guthrie Research Institute.

Measurements and results: Activation of mAChR with the agonist carbachol (10 µM, 1.5 h) significantly increases adhesion of the SCC-9 SCLC cell line to the ECM proteins laminin and collagen types I and IV. In contrast, mAChR activation does not alter the adhesion of SCC-9 cells to vitronectin, fibronectin, poly-L-lysine, or bovine serum albumin. Carbachol also does not alter the adhesion of NCI-H345 SCLC cells that lack functional mAChR. Preincubation of SCC-9 cells with the AIIB2 blocking antibody to β1-integrin inhibits mAChR-induced adhesion to ECM proteins. Immunofluorescence analysis indicates that mAChR activation does not alter the surface expression of β1-integrins by SCC-9 cells. Direct stimulation of protein kinase C (PKC) by treatment with phorbol 12-myristate 13-acetate (PMA) (10 nM, 1.5 h) increases the adhesion of both the SCC-9 and NCI-H345 cell lines to ECM proteins. These results indicate that direct activation of PKC or stimulation of M3 mAChR (which results in increased PKC activity) increases the binding activity of β1-integrins, resulting in increased adhesion of SCLC cells to ECM proteins.

Conclusions: The ability of mAChR to regulate SCLC proliferation and adhesion suggests that activation of these receptors may be used to alter SCLC tumorigenesis and metastasis.


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