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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]

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