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

Abstract

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) 165 significantly decreased the proapoptotic and antimitotic effect of transfected or secreted SEMA3B on lung and breast cancer cells. VEGF 165 binds to neuropilin, receptors for SEMA3B, and we found that SEMA3B competed for binding of 125 I-VEGF165 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 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 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.

Pulmonary Epithelial Neuropilin-1 Deletion Enhances Development of Cigarette Smoke–induced Emphysema

“…Because epithelial cells are the primary source of VEGF in lung lavage, an alternative explanation linking conditional epithelial Nrp1 deletion and decreased lavage VEGF concentrations in CS-exposed CCSPrtTA/tetO-Cre/Nrp1 flox/flox mice could be that enhanced epithelial cell death decreases VEGF production. Furthermore, although several investigators have demonstrated that the effects of Nrp1 on cell proliferation and death may depend on how this receptor modulates the balance between VEGF and Sema3 signaling (17,26), other studies also demonstrate that Nrp1 may alter cell survival independent of its effects on VEGFR activation (22,(80)(81)(82).…”

“…Nrp1 may modulate the balance between VEGF and Sema3 signaling to alter cell proliferation and death in nonepithelial cell types (17,26). Both Nrp1 ligands, VEGF, and Sema3A, have independently been shown to contribute to alveolar septation (24,(27)(28)(29)(30) and vascular patterning (23,27,31), and human (32,33), animal (34)(35)(36)(37), and in vitro (38) studies support a possible role for VEGF in protection from acute lung injury and preservation of alveolar cell survival (39).…”

The brain within the tumor: new roles for axon guidance molecules in cancers

“…36 An antiproliferative activity of SEMA3B has been shown for breast cancer cell lines. 39 In addition, in lung and breast cancer cell lines, SEMA3B effects are antagonized by the angiogenic factor vascular endothelial growth factor (VEGF) 165,39 suggesting that SEMA3B tumor suppressor activity involves VEGF signaling. Ovarian adenocarcinoma cells (HEY cells) also express 25-fold less SEMA3B than in normal human ovary and have decreased tumorigenic properties in xenograft model.…”

“…Last, SEMA3B may also act as a mediator of p53-suppressor activity in glioblastoma cell lines. 41 The emerging model 39 suggests that in premalignant cells, the activation of the p53 pathway leads to a decrease of SEMA3B expression and/or an overexpression of its antagonist VEGF, therefore allowing cancer cells to survive and 35 for a review) but it is overexpressed in migrating lung cancer cells. 42 SEMA3F inhibits the attachment and spreading of breast cancer cells (MCF7) apparently through interaction with neuropilin-1 and not neuropilin-2.…”

CLCP1 interacts with semaphorin 4B and regulates motility of lung cancer cells

“…SEMA3B and SEMA3F, which are localized at the 3p21.3 locus, are frequently deleted in lung cancers and have been found to suppress tumor cell proliferation Xiang et al, 2002;Castro-Rivera et al, 2004). In contrast, class IV semaphorins do not show 293T cells were transfected with CLCP1-HA, SEMA4B-myc and/or SEMA4B-Fc-myc, then treated with a proteasome inhibitor, MG-132 (SIGMA-ALDRICH, St Louis, MO, USA), at 10 mM for 24 h. The expression levels of CLCP1 and SEMA4B proteins were then investigated using anti-HA and anti-myc antibodies.…”