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.
Highlights
Antiangiogenic agents have been widely considered as the fourth modality in cancer treatment, together with surgery, chemotherapy, and radiotherapy
Endostatin has novel ATPase activity Walker motifs are found in a broad range of ATPases, and thereby provide predictive value for ATPases [31]
Through detailed examination of human endostatin sequence, we found that endostatin comprises a Walker A motif variant (GXXGXXK; ref. 32) and a Walker B motif (Fig. 1A, I and II), suggesting that endostatin may display ATPase activity
Summary
Antiangiogenic agents have been widely considered as the fourth modality in cancer treatment, together with surgery, chemotherapy, and radiotherapy. Endostatin, as an endogenous antiangiogenic inhibitor [1], exhibits potent antitumor activities in various mouse models [2] and receives CFDA (China Food and Drug Administration) approval as a new drug for the treatment of non–small cell lung cancer (NSCLC) patients in clinic [3]. This drug is widely used in China and shows profound clinical efficacy [4,5,6]. Endostatin diminishes the proliferation, migration, and tube formation of
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