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.

CDX2 dose-dependently influences the gene regulatory network underlying human extraembryonic mesoderm development

“…6D, Table S4). Like ANK3 and ANGPT1 , TMSB10 influences VEGF expression, specifically inhibiting VEGF-induced endothelial cell proliferation, migration, and invasion (Lee et al ., 2005; Pan et al ., 2020). Five of these 9 genes were also significantly upregulated in CDX2-Het and 0 were upregulated in TBXT-Het (Table S4).…”

Can thymosin beta 10 function both as a non-invasive biomarker and chemotherapeutic target in human colorectal cancer?

“…Zhang et al [ 9 ] reported that the up-regulated TMSB10 contributed to the migration and invasion of breast cancer cells, and promoted cell proliferation of breast cancer by accelerating the cell cycle progression of breast cancer cells. In contrast, a down-regulated expression of TMSB10 was observed in kidney chromophobe, acute myeloid leukemia, and brain lower grade glioma, and the knockdown of TMSB10 in ovarian cancer cells promoted tumor growth and proliferation [ 18 ]. These findings revealed differences of TMSB10 expression in different cancers.…”

Whole-Exome sequencing analysis identified TMSB10/TRABD2A locus to be associated with carfilzomib-related cardiotoxicity among patients with multiple myeloma

“…A recent study showed that the actin-binding protein TMSB10 was upregulated in dysfunctional endothelial dysfunction in acute myocardial infarction (AMI), and endothelial dysfunction is considered one of the primary factors in the progression of atherothrombosis in AMI ( 35 ). Another study on mice found that TMSB10 can inhibit vascular endothelial growth factor (VEGF) expression by inhibiting the Ras-ERK signaling pathway leading to the suppression of vascular formation, especially in tumor formation ( 36 ).…”