Gadd45a Suppresses Tumor Angiogenesis via Inhibition of the mTOR/STAT3 Protein Pathway*

Abstract

Gadd45a, a p53-regulated and DNA damage-inducible gene, is implicated in protection against tumor malignancy, although the underlying mechanism remains to be defined further. Here we demonstrate that Gadd45a plays an important role in suppression of tumor angiogenesis. Gadd45a deletion significantly increases microvessel density in tumors and stimulates an angiogenic response in a chicken embryo chorioallantoic membrane assay. Disruption of endogenous Gadd45a promotes tube formation and migration of endothelial cells. We further show that Gadd45a deletion increases phosphorylation of STAT3 at Ser-727 and, in turn, elevates the STAT3 transcriptional activity. This process substantially induces both expression and secretion of VEGFa, a STAT3 responsive gene, and promotes tumor angiogenesis. Interestingly, Gadd45a is able to physically associate with mammalian target of rapamycin (mTOR), a kinase that mediates Ser-727 phosphorylation of STAT3. The interaction of Gadd45a with mTOR suppresses STAT3 phosphorylation at Ser-727 and leads to down-regulated expression of VEGFa. Further analysis reveals that Gadd45a overexpression attenuates the association between mTOR and STAT3, whereas Gadd45a disruption strengthens this interaction, indicating that Gadd45a suppression of STAT3 phosphorylation is mainly through the dissociation of mTOR with STAT3. Taken together, these findings provide the first evidence that Gadd45a inhibits tumor angiogenesis via blocking of the mTOR/STAT3 pathway.