This Article Full Text Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Potiron, V. A. Articles by Drabkin, H. A. Search for Related Content PubMed PubMed Citation Articles by Potiron, V. A. Articles by Drabkin, H. A.

Semaphorin SEMA3F Affects Multiple Signaling Pathways in Lung Cancer Cells

¹ Division of Medical Oncology, University of Colorado Health Sciences Center, Aurora, Colorado; ² CNRS UMR 6187, Institut de Physiologie et Biologie Cellulaires, Faculté des Sciences de Poitiers, Poitiers, France; ³ Department of Vascular Biology and Angiogenesis Research, Tumor Biology Center, Freiburg, Germany; and ⁴ Joint Research Division Vascular Biology, Medical Faculty Mannheim, University of Heidelberg and German Cancer Research Center, Heidelberg, Germany

Requests for reprints: Harry A. Drabkin, Division of Hematology/Oncology, Medical University of South Carolina, P. O. Box 250623, 96 Jonathan Lucas Street, Charleston, SC 29425. Phone: 843-792-8297; E-mail: drabkin{at}musc.edu.

Loss of SEMA3F occurs frequently in lung cancer and correlates with advanced stage of disease. We previously reported that SEMA3F blocked tumor formation by H157 lung cancer cells in a rat orthotopic model. This was associated with loss of activated _Vß₃ integrin, impaired cell adhesion to extracellular matrix components, and down-regulation of phospho-extracellular signal-regulated kinase 1/2 (ERK1/2). These results suggested that SEMA3F might interfere with integrin outside-in signaling. In the present report, we found that SEMA3F decreased adhesion to vitronectin, whereas integrin-linked kinase (ILK) kinase activity was down-regulated in SEMA3F-expressing H157 cells. Exposure to SEMA3F-conditioned medium led to diminution of phospho-ERK1/2 in four of eight lung cancer cell lines, and ILK silencing by small interfering RNA led to similar loss of phospho-ERK1/2 in H157 cells. Moreover, SEMA3F expression (with constitutive and inducible systems) also reduced AKT and signal transducer and activator of transcription 3 (STAT3) phosphorylation independently of ILK-ERK1/2. These signaling changes extended downstream to hypoxia-inducible factor-1 (HIF-1) protein and vascular endothelial growth factor (VEGF) mRNA levels, which were both reduced in three of four SEMA3F-transfected cell lines. Mechanistically, the effects on HIF-1 were consistent with inhibition of its AKT-driven protein translation initiation, with no effect on HIF-1 mRNA level or protein degradation. Furthermore, when H157 cells were injected s.c. in nude mice, tumors derived from SEMA3F-expressing cells showed lower microvessel density and tumor growth. These results show that SEMA3F negatively affects ILK-ERK1/2 and AKT-STAT3 signaling, along with inhibition of HIF-1 and VEGF. These changes would be anticipated to contribute significantly to the observed antitumor activity of SEMA3F. [Cancer Res 2007;67(18):8708–15]

This article has been cited by other articles:

				L. Capparuccia and L. Tamagnone Semaphorin signaling in cancer cells and in cells of the tumor microenvironment - two sides of a coin J. Cell Sci., June 1, 2009; 122(11): 1723 - 1736. [Abstract] [Full Text] [PDF]

				E. Castro-Rivera, S. Ran, R. A. Brekken, and J. D. Minna Semaphorin 3B Inhibits the Phosphatidylinositol 3-Kinase/Akt Pathway through Neuropilin-1 in Lung and Breast Cancer Cells Cancer Res., October 15, 2008; 68(20): 8295 - 8303. [Abstract] [Full Text] [PDF]

				C. Rolny, L. Capparuccia, A. Casazza, M. Mazzone, A. Vallario, A. Cignetti, E. Medico, P. Carmeliet, P. M. Comoglio, and L. Tamagnone The tumor suppressor semaphorin 3B triggers a prometastatic program mediated by interleukin 8 and the tumor microenvironment J. Exp. Med., May 12, 2008; 205(5): 1155 - 1171. [Abstract] [Full Text] [PDF]

				G. Serini, L. Napione, M. Arese, and F. Bussolino Besides adhesion: new perspectives of integrin functions in angiogenesis Cardiovasc Res, May 1, 2008; 78(2): 213 - 222. [Abstract] [Full Text] [PDF]

				M. Narazaki, M. Segarra, and G. Tosato Neuropilin-2: A New Molecular Target for Antiangiogenic and Antitumor Strategies J Natl Cancer Inst, January 16, 2008; 100(2): 81 - 83. [Full Text] [PDF]