Semaphorin Signaling is Regulated by Transferrin through an IGFBP‐3 and IGF‐1 Dependent Pathway

Semaphorin (sema)3C up‐regulation increased invasion and adhesion of PC‐3 prostate cancer cells, while sema3E up‐regulation decreased invasion and adhesion. Previously we found that 5 μg/mL of transferrin (Tf) modulated the invasive and adhesive properties of sema3E and sema3C transfected PC‐3 cells. Tf increased invasion and adhesion in sema3E cells, but did not significantly alter invasion and adhesion of sema3C cells as compared to controls. Tf inhibits insulin‐like growth factor binding protein 3 (IGFBP3), a tumor suppressor that regulates proliferation, adhesion and migration. The addition of 0.15 μg/mL IGFBP3 to sema3C and sema3E transfectants did not significantly affect invasion or adhesion when compared to cells grown without IGFBP3. However, the modulating effects of Tf were negated when cells were cultured with both Tf and IGFBP3. Furthermore, IGFBP3 inhibits insulin‐like growth factor 1 (IGF‐1) that regulates migration, adhesion and invasion. The semaphorin transfectants were cultured with 0.1 μg/mL of IGF‐1, and these conditions mimicked the effect of Tf on the invasive and adhesive properties of sema3C and sema3E. These data suggest that Tf modulation of semaphorins occurs through an IGFBP3‐ and IGF‐1‐dependent pathway. (Supported by NIH grant CA101035).