Translation of the
small G protein RhoA in neurons is regulated by the eukaryotic translation
initiation factor eIF4E. Here we show that this translation factor also regulates RhoA expression and activity in
breast cancer cells. The introduction of
eIF4E into
breast tumor cells increased
RhoA protein levels, while expression of an
eIF4E siRNA reduced RhoA expression. Previous studies indicate that the axon repulsion factor Semaphorin3A (
Sema3A) stimulates the eIF4E-dependent translation of RhoA in neurons, and
breast tumor cells support autocrine
Sema3A signaling. Accordingly, we next examined if autocrine
Sema3A signaling drives eIF4E-dependent RhoA translation in
breast cancer cells. The incubation of
breast tumor cells with recombinant
Sema3A rapidly increased
eIF4E activity,
RhoA protein levels, and RhoA activity. This
Sema3A activity was blocked in
tumor cells expressing an
shRNA-specific for the
Sema3A receptor,
Neuropilin-1 (NP-1), as well as in cells incubated with an
eIF4E inhibitor. Importantly,
RhoA protein levels were reduced in
Sema3A shRNA-expressing compared to control
shRNA-expressing
breast tumor cells, demonstrating that autocrine
Sema3A increases RhoA expression in
breast cancer. Considering that
Sema3A suppresses axon extension by stimulating RhoA translation, we next examined if the
Sema3A/RhoA axis impacts
breast tumor cell migration. The incubation of control
breast tumor cells, but not RhoA
shRNA-expressing cells, with rSema3A significantly reduced their migration. Collectively, these studies indicate that
Sema3A impedes
breast tumor cell migration in part by stimulating RhoA. These findings identify common signaling pathways that regulate the navigation of neurons and
breast cancer cells, thus suggesting novel targets for suppressing
breast tumor cell migration.