Semaphorin 5A and plexin-B3 regulate human glioma cell motility and morphology through Rac1 and the actin cytoskeleton

Abstract

Semaphorins are implicated in glioma progression, although little is known about the underlying mechanisms. We have reported plexin-B3 expression in human gliomas, which upon stimulation by Sema5A causes significant inhibition of cell migration and invasion. The concomitant inactivation of Rac1 is of mechanistic importance because forced expression of constitutively active Rac1 abolishes these inhibitory effects. Furthermore, Sema5A induces prominent cell collapse and ramification of processes reminiscent of astrocytic morphology, which temporally associate with extensive disassembly of actin stress fibers and disruption of focal adhesions, followed by accumulation of actin patches in protrusions. Mechanistically, Sema5A induces transient protein kinase C (PKC) phosphorylation of fascin-1, which can reduce its actin-binding/bundling activities and temporally parallels its translocation from cell body to extending processes. PKC inhibition or fascin-1 knockdown is sufficient to abrogate Sema5A-induced morphological differentiation, whereas the process is hastened by forced expression of fascin-1. Intriguingly, Sema5A induces re-expression of glial fibrillary acidic protein (GFAP), which when silenced restricts differentiation of glioma cells to bipolar instead of multipolar morphology. Therefore, we hypothesize complementary functions of fascin-1 and GFAP in the early and late phases of Sema5A-induced astrocytic differentiation of gliomas, respectively. In summary, Sema5A and plexin-B3 impede motility but promote differentiation of human gliomas. These effects are plausibly compromised in high-grade human astrocytomas in which Sema5A expression is markedly reduced, hence leading to infiltrative and anaplastic characteristics. This is evident by increased invasiveness of glioma cells when endogenous Sema5A is silenced. Therefore, Sema5A and plexin-B3 represent potential novel targets in counteracting glioma progression.

Molecular Mechanisms of Glioma Cell Motility

“…Downstream signaling of Sema involves RhoA, RAC-1, and cofilin, leading to the reorganization of the cytoskeleton (142). In GBM cells, inactivation of RhoA by Sema3F leads to the collapse of the cytoskeleton, whereas inhibition of Sema3F promotes cell motility (143,144). Similar effects have been observed for Sema3G (145), and higher expression of Sema3G in GBM patients has been associated with a better prognosis (146).…”

The role of the semaphorins in cancer

“…[87][88][89][90] Since many types of tumor cells express semaphorin receptors it is not surprising that semaphorins have been found to inhibit the proliferation and metastatic spread of tumor cells by affecting tumor cells in a variety of ways. 71,[91][92][93] In addition some semaphorins have been found to inhibit tumor progression as a result of their effects on the tumor microenvironment. Processes such as the recruitment of various stromal cells such as macrophages to the tumor microenvironment can be affected by various semaphorins 94 but perhaps best studied are the effects of some semaphorins on tumor angiogenesis.…”

Elevated Semaphorin 5A correlated with Th1 polarization in patients with chronic immune thrombocytopenia

“…Plexin-B family was reported to elicit two distinct signaling pathways. One negatively regulates integrin function and leads to cellular collapse, and another triggers the tyrosine kinase activity and leads to the invasive growth program [22,36]. Therefore, we presumed that plexin-B3 might negatively regulate cell signaling in chronic ITP.…”