Endostatin Has ATPase Activity, Which Mediates Its Antiangiogenic and Antitumor Activities

Abstract

Endostatin is an endogenous angiogenesis inhibitor with broad-spectrum antitumor activities. Although the molecular mechanisms of endostatin have been extensively explored, the intrinsic biochemical characteristics of endostatin are not completely understood. Here, we revealed for the first time that endostatin embedded novel ATPase activity. Moreover, mutagenesis study showed that the ATPase activity of endostatin mutants positively correlated with effects on endothelial cell activities and tumor growth. E-M, an endostatin mutant with higher ATPase activity than that of wild-type (WT) endostatin, significantly increased endostatin-mediated inhibitory effects on endothelial cell proliferation, migration, tube formation, and adhesion. In vivo study showed that E-M displayed enhanced antitumor effects compared with WT. On the other hand, K96A, K96R, and E176A, endostatin mutants with lower ATPase activities than that of WT, showed reduced or comparable effects on targeting both in vitro endothelial cell activities and in vivo tumor angiogenesis and tumor growth. Furthermore, endostatin and its mutants exhibited distinct abilities in regulations of gene expression (Id1, Id3), cell signaling (Erk, p38, and Src phosphorylation), and intracellular ATP levels. Collectively, our study demonstrates that endostatin has novel ATPase activity, which mediates its antiangiogenic and antitumor activities, suggesting that construction of endostatin analogues with high ATPase activity may provide a new direction for the development of more potent antiangiogenic drugs.

Blockade of extracellular NM23 or its endothelial target slows breast cancer growth and metastasis

“…When these treatments are compared at the time of sacrifice at the end of the study, there is a clear reduction on the presence of lung metastases (Figure 6). Comparisons to endostatin, known to prevent metastases in the mouse [63,64] and now known to possess ATPase activity [65] consistent with an action in the NM23:P2Y 1 R pathway, are encouraging offering both a comparative benefit as well as suggesting a mechanistic role for endostatin consistent with our hypothesis.…”

Endostatin's emerging roles in angiogenesis, lymphangiogenesis, disease, and clinical applications

“…Although not extensively studied, the results of in vivo experiments support endostatin’s anti-lymphangiogenic role based on its inhibition of bFGF-induced lymphangiogenesis [165]. Endostatin has recently been found to have intrinsic ATPase activity in vivo , which mediates its anti-angiogenic and anti-tumoral activities by further inhibiting endothelial cell proliferation, migration, tube formation, and adhesion [166]. …”

Clinical observation of recombinant human endostatin in treating relapsed refractory multiple myeloma

“…exerts a wide-ranging antitumour effect via suppression of pathological angiogenesis and suppression of tumours proliferation and metastasis. [12][13][14] The rhES is a novel antiangiogenic agent that is derived from endostatin by adding nine amino acids to the peptide chain N-terminal of endostatin, with a longer half-life period, heightened purity, bioactivity and stability. 15,16 It has been revealed that rhES improved antitumour validity when combined with cytotoxic drugs in Lewis lung carcinoma, 17 and rhES enhanced antitumour efficacy when combined with conventional chemotherapy.…”