Thymosin β10 inhibits angiogenesis and tumor growth by interfering with Ras function

Abstract

Thymosin β10 is a monomeric actin sequestering protein that regulates actin dynamics. Previously, we and others have shown that thymosin β10 acts as an actin-mediated tumor suppressor. In this study, we show that thymosin β10 is not only a cytoskeletal regulator, but that it also acts as a potent inhibitor of angiogenesis and tumor growth by its interaction with Ras. We found that overexpressed thymosin β10 significantly inhibited vascular endothelial growth factor-induced endothelial cell proliferation, migration, invasion, and tube formation in vitro. Vessel sprouting was also inhibited ex vivo. We further show that thymosin β10 directly interacted with Ras. This interaction resulted in inhibition of the Ras downstream mitogen-activated protein kinase/extracellular signal-regulated kinase kinase signaling pathway, leading to decreased vascular endothelial growth factor production. Thymosin β10 injected into a xenograft model of human ovarian cancer in nude mice markedly inhibited tumor growth and reduced tumor vascularity. In contrast, a related thymosin family member, thymosin β4, did not bind to Ras and showed positive effects on angiogenesis. These findings show that the inhibition of Ras signal transduction by thymosin β10 results in antiangiogenic and antitumor effects, suggesting that thymosin β10 may be valuable in anticancer therapy.