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.
Highlights
Gadd45a inhibits tumor initiation and progression via multiple pathways
The two types of xenograft tumors were immunostained with PCNA and BCL2-associated X protein (BAX) antibodies for evaluation of proliferation and apoptosis
It is noted that PCNA expression was greatly increased in Gadd45aϪ/Ϫ Mouse embryonic fibroblasts (MEFs) tumors compared with Gadd45aϩ/ϩ ones (Fig. 1, e and f), whereas Gadd45aϩ/ϩ MEF tumors expressed a higher level of BAX than the Gadd45aϪ/Ϫ ones (Fig. 1, g and h)
Summary
Results: Gadd45a disruption stimulates tumor angiogenesis by increasing VEGFa expression and STAT3 transcriptional activity. 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. Gadd45a, a ubiquitously expressed and DNA damage-responsive protein, is induced by varieties of genotoxic stress agents such as UV radiation, ionizing radiation, methyl methanesulfonate, and hydroxyurea It plays important roles in suppressing cell proliferation, mediating cell cycle arrest, promoting apoptosis, inducing DNA repair, and stabilizing genomics. We demonstrate that Gadd45a disruption increases expression of VEGFa and promotes formation of tumor blood vessels. Gadd45a expression disrupts the interaction between mTOR and STAT3 and suppresses phosphorylation of STAT3 at Ser727 These findings provide the first demonstration that Gadd45a plays a negative role in tumor angiogenesis by blocking the mTOR/STAT3 pathway
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