Semaphorin 3B (SEMA3B) induces apoptosis in lung and breast cancer, whereas VEGF sub(165) antagonizes this effect

• Published in: Proceedings of the National Academy of Sciences - PNAS 2004-08, Vol.101 (31), p.11432-11437
• Main Authors: Castro-Rivera, Emely, Ran, Sophia, Thorpe, Philip, Minna, John D
• Format: Article
• Language: English
• ISSN: 0027-8424; 1091-6490

Semaphorin 3B (SEMA3B) is a secreted member of the semaphorin family, important in axonal guidance. We and others have shown that SEMA3B can act as a tumor suppressor by inducing apoptosis either by reexpression in tumor cells or applied as a soluble ligand. The common method of inactivation of SEMA3B is by allele loss and tumor-acquired promoter methylation. We studied the mechanism of SEMA3B-induced tumor cell apoptosis and found that vascular endothelial growth factor (VEGF) sub(165) significantly decreased the proapoptotic and antimitotic effect of transfected or secreted SEMA3B on lung and breast cancer cells. VEGF sub(165) binds to neuropilin, receptors for SEMA3B, and we found that SEMA3B competed for binding of super(125)I-VEGF sub(165) to lung and breast cancer cells. We also found that small interfering RNA knockdown of tumor-produced VEGF-A or the use of an anti-VEGF neutralizing antibody (Ab) significantly inhibited tumor cell growth in vitro. By contrast, VEGF sub(121), a VEGF variant that lacks binding to neuropilin (NP)-1 or NP-2 receptors, was not expressed in tumor cells and had no effect on SEMA3B growth-suppressing activities. In conclusion, we hypothesize that VEGF sub(165), produced by tumor cells, acts as an autocrine survival factor and that SEMA3B mediates its tumor-suppressing effects, at least in part, by blocking this VEGF autocrine activity.