Thymosin {beta}(10) inhibits angiogenesis and tumor growth by interfering with Ras function.
Thymosin beta(10) is a monomeric actin sequestering protein that regulates actin dynamics. Previously, we and others have shown that thymosin beta(10) acts as an actin-mediated tumor suppressor. In this study, we show that thymosin beta(10) 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 beta(10) 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 beta(10) 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 beta(10) 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 beta(4), did not bind to Ras and showed positive effects on angiogenesis. These findings show that the inhibition of Ras signal transduction by thymosin beta(10) results in antiangiogenic and antitumor effects, suggesting that thymosin beta(10) may be valuable in anticancer therapy.
Lee
Seung-Hoon
SH
Molecular Therapy Research Center, Samsung Medical Center, School of Medicine, Sung Kyun Kwan University, Seoul, Korea.
Son
Myung Jin
MJ
Oh
Sun-Hee
SH
Rho
Seung-Bae
SB
Park
Kyungsook
K
Kim
Yung-Jin
YJ
Park
Mi-Sun
MS
Lee
Je-Ho
JH
D000199:Actins / Q000378:metabolism; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D003599:Cytoskeleton / Q000502:physiology; D004261:DNA Replication / Q000187:drug effects; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D011905:Genes, ras / Q000502:physiology*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects; D013947:Thymosin / Q000494:pharmacology*; D014471:Umbilical Veins
D000199:Actins; D020533:Angiogenesis Inhibitors; D013947:Thymosin; C039302:thymosin beta(10)