E-cadherin negatively regulates neoplastic growth in non-small cell lung cancer: role of Rho GTPases

• Published in: Oncogene Vol. 29; no. 19; pp. 2760 - 2771
• Main Authors: Asnaghi, L, Vass, W C, Quadri, R, Day, P M, Qian, X, Braverman, R, Papageorge, A G, Lowy, D R
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 13.05.2010; Nature Publishing Group
• Subjects: 631/80/79/1902; 692/420/755; 692/699/67/1612/1350; Animals; Apoptosis; beta Catenin - metabolism; Biological and medical sciences; Cadherins; Cadherins - metabolism; Carcinoma, Non-Small-Cell Lung - enzymology; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - metabolism; Carcinoma, Non-Small-Cell Lung - pathology; Care and treatment; cdc42 GTP-Binding Protein - metabolism; Cdc42 protein; Cell adhesion & migration; Cell Biology; Cell growth; Cell Line, Tumor; Cell migration; Cell Movement; Cell physiology; Cell Proliferation; Cell surface; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cellular signal transduction; E-cadherin; ErbB Receptors - metabolism; Fundamental and applied biological sciences. Psychology; Gene expression; Gene Expression Regulation, Neoplastic; Genetic aspects; GTPase-Activating Proteins - metabolism; Guanosine triphosphatase; Health aspects; Human Genetics; Humans; Internal Medicine; Lung cancer; Lung cancer, Non-small cell; Lung Neoplasms - enzymology; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Medical sciences; Medicine; Medicine & Public Health; Molecular and cellular biology; Non-small cell lung carcinoma; Oncology; original-article; Physiological aspects; Pneumology; Proteins; rho GTP-Binding Proteins - metabolism; rhoA GTP-Binding Protein - metabolism; RhoA protein; Signal Transduction; siRNA; Small cell lung carcinoma; Therapeutic targets; Transfection; Tumor Suppressor Proteins - metabolism; Tumors; Tumors of the respiratory system and mediastinum; Wnt protein; Wnt Proteins - metabolism; β-Catenin; United States; cell migration; Rho-family GTPases; tumorigenesis; NSCLC; E-cadherin; Lung disease; Enzyme; Respiratory disease; Triphosphoric monoester hydrolases; Growth; Migration; dGTPase; Esterases; Malignant tumor; non-small cell lung carcinoma; Carcinogenesis; Regulation(control); Hydrolases; Bronchus disease; E Cadherin; Cancer
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2010.39

Non-small cell lung cancers (NSCLC) that express the cell surface adhesion protein E-cadherin may carry a better prognosis than E-cadherin-negative tumors. Here, we found substantial inhibition of anchorage-independent growth in soft agar and cell migration in each of four NSCLC lines stably transfected with E-cadherin. The inhibitory effects were independent of the EGFR and β-catenin/Wnt-signaling pathways. However, E-cadherin expression was associated with an adhesion-dependent reduction in the activity of Rho family proteins, RhoA in two lines and Cdc42 in the other two. The reduction of RhoA activity was dependent on DLC-1 Rho-GAP and p190 Rho-GAP and associated with an increase in a membrane-associated p190 Rho-GAP/p120 Ras-GAP complex. In parental cells with high levels of RhoA-GTP, siRNA-mediated knock-down of RhoA reduced cell migration and agar growth in a manner analogous to E-cadherin. In parental cells with high levels of Cdc42-GTP, transfection of a Cdc42 dominant-negative mutant reduced cell growth and migration similarly to cells expressing E-cadherin. Thus, E-cadherin can negatively regulate cell proliferation and migration in NSCLC by reducing the level of the predominant active form of Rho family protein, RhoA or Cdc42. These proteins can be considered downstream effectors of E-cadherin and might represent therapeutic targets in some NSCLC.