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Identification of Amino Acids Essential for the Antiangiogenic Activity of Tumstatin and Its Use in Combination Antitumor Activity

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Identification of Amino Acids Essential for the Antiangiogenic Activity of Tumstatin and Its Use in Combination Antitumor Activity Identification of amino acids essential for the antiangiogenic activity of tumstatin and its use in combination antitumor activity Hans Petter Eikesdal*†, Hikaru Sugimoto*†, Gabriel Birrane‡, Yohei Maeshima*, Vesselina G. Cooke*, Mark Kieran§, and Raghu Kalluri*¶ʈ *Division of Matrix Biology, Department of Medicine, and ‡Division of Experimental Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215; §Department of Pediatric Oncology, Dana–Farber Cancer Institute, Boston, MA 02215; and ¶Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston and Harvard–Massachusetts Institute of Technology Division of Health Sciences and Technology, Cambridge, MA 02139 Communicated by James D. Watson, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, August 13, 2008 (received for review April 24, 2008) Tumstatin is an angiogenesis inhibitor that binds to ␣v␤3 integrin cells in vitro, and the inhibition of protein synthesis in endothelial and suppresses tumor growth. Previous deletion mutagenesis cells is mediated by the tumstatin peptide (3, 8). studies identified a 25-aa fragment of tumstatin (tumstatin pep- The current experiments were designed to identify the critical tide) with in vitro antiangiogenic activity. Here, we demonstrate amino acids within tumstatin that confer antiangiogenesis activ- that systemic administration of this tumstatin peptide inhibits ity and define the antiangiogenic and antitumor activity of tumor growth and angiogenesis. Site-directed mutagenesis iden- tumstatin peptide. Additionally, we explored the endothelial tified amino acids L, V, and D as essential for the antiangiogenic binding characteristics of the tumstatin peptide in both the in activity of tumstatin. The tumstatin peptide binds to ␣v␤3 integrin vitro and in vivo settings. Combination of tumstatin peptide with on proliferating endothelial cells and localizes to select tumor anti-VEGF antibody was also explored for possible improvement endothelium in vivo. Using 3D molecular modeling, we identify a in antitumor efficacy. putative interaction interface for tumstatin peptide on ␣v␤3 inte- grin. The antitumor activity of the tumstatin peptide, in combina- Results tion with bevacizumab (anti-VEGF antibody), displays significant Tumstatin Peptide Inhibits Tumor Growth. A putative structure improvement in efficacy against human renal cell carcinoma xeno- representing tumstatin and containing the tumstatin peptide is grafts when compared with the single-agent use. Collectively, our shown in Fig. 1A. Tumstatin peptide significantly inhibits the results demonstrate that tumstatin peptide binds specifically to the growth of SCC-PSA1 teratocarcinomas, when compared with tumor endothelium, and its antiangiogenic action is mediated by sham treatment (Fig. 1B). To test for tumstatin peptide speci- ␣v␤3 integrin, and, in combination with an anti-VEGF antibody it ficity, an efficacy experiment was conducted by using a selective exhibits enhanced tumor suppression of renal cell carcinoma. antitumstatin peptide antibody. The use of antitumstatin peptide but not the preimmune sera significantly reversed the effects of angiogenesis ͉ ␣v␤3 integrin ͉ bevacizumab ͉ tumstatin peptide the tumstatin peptide (Fig. 1C), indicating that tumstatin peptide specifically inhibits tumor growth (9). umor angiogenesis is a hallmark of tumor growth and Tmetastasis (1). There are currently several antiangiogenic Site-Directed Mutagenesis of Tumstatin Peptide Identifies L, V, and D agents approved for human cancer therapy, but their effect is as the Critical Amino Acids for Antiangiogenesis and Antitumor modest and short-acting, with therapy resistance generally de- Activity. Homology information derived from sequence compar- veloping within a few months. Thus, further research is required ison between tumstatin and the NC1 domain of ␣5 chain of type to improve the efficacy of antiangiogenic therapy and to identify IV collagen, which lacks antiangiogenic activity (10), led to the genetic alterations that are likely to predict the therapeutic identification of amino acids that might contribute to the anti- outcome for cancer patients. angiogenic activity of tumstatin. Using rationale site-directed We previously identified and characterized tumstatin as an mutagenesis, we embarked on mapping the crucial amino acids endogenous antiangiogenic agent derived from the noncollag- within the tumstatin peptide and constructed seven different enous (NC1) domain of the ␣3 chain of type IV collagen (2). sequence variants. Within the 25 aa of tumstatin, the L, V, and Tumstatin is an inhibitor of endothelial cell proliferation and D amino acids were found to be essential for the antiangiogenic suppresses the growth of various tumor types in mice (2, 3). It activity (Table 1). In proliferation assays, the MIN mutant binds to endothelial cells via ␣v␤3 integrin, and this binding is peptide (tumstatin mutant peptide) does not exhibit any activity, speculated to be important for its antiangiogenic activity [see whereas the tumstatin peptide inhibits proliferation of endothe- supporting information (SI) Table S1]. Integrins are a family of lial cells by Ϸ50% (Fig. 1D). Next, we demonstrate that the cell adhesion molecules. All integrins are heterodimeric trans- tumstatin mutant peptide is incapable of inhibiting growth of membrane proteins, always consisting of an ␣ and a ␤ subunit, and ␣v␤3 integrin on endothelial cells is one such heterodimer (4). The heterodimer formation is essential for mediating out- Author contributions: R.K. designed research; H.P.E., H.S., G.B., Y.M., and V.G.C. performed research; H.P.E., H.S., M.K., and R.K. analyzed data; and H.P.E., H.S., and R.K. wrote the side-in cell signaling (5). The efficacy of tumstatin is profoundly paper. 3 increased in tumors above the size of 500 mm , correlating with Conflict of interest statement: Beth Israel Deaconess Medical Center has licensed the increased endothelial ␣v␤3 integrin expression at this stage (6). intellectual property surrounding tumstatin to EAI Corporation and is also an equity owner Although the C-terminal half of tumstatin exhibits direct tumor along with R.K. cell cytotoxicity, the antiangiogenic activity of tumstatin resides †H.P.E. and H.S. contributed equally to this work. in the N-terminal half, restricted to amino acids 74–98 and ʈTo whom correspondence should be addressed. E-mail: [email protected]. termed the T7 peptide (3, 7). The T7 peptide (referred to as This article contains supporting information online at www.pnas.org/cgi/content/full/ tumstatin peptide in this report) and the full length tumstatin 0807055105/DCSupplemental. protein have an equivalent antiproliferative effect on endothelial © 2008 by The National Academy of Sciences of the USA 15040–15045 ͉ PNAS ͉ September 30, 2008 ͉ vol. 105 ͉ no. 39 www.pnas.org͞cgi͞doi͞10.1073͞pnas.0807055105 Downloaded by guest on September 28, 2021 A BC D E F Fig. 2. Identification of amino acids responsible for the anti-angiogenesis property of tumstatin. (A and B) Electrostatic surface representation of the tumstatin and the tumstatin mutant protein homology models. Surface charges are shown as: blue, positive; and red, negative. The tumstatin peptide region is indicated by the yellow rectangle, and the point-mutated residues are indicated by arrows. In the tumstatin peptide mutant and tumstatin mutant protein, amino acids L (78), V (82) and D (84) were replaced with amino Fig. 1. Tumstatin peptide inhibits tumor growth and tumor angiogenesis. acids M, I and N, respectively. The V to I mutation is not visible in this (A) Predicted secondary structure of tumstatin. The tumstatin peptide is orientation of the surface model (indicated by gray letters). (C) The impor- indicated by the yellow box and highlighted in green. Secondary structure tance of tumstatin peptide sequence for the anti-endothelial activity of elements are colored beige (strands), purple (␣-helices), and gray (coil) and tumstatin. Cell proliferation in C-PAE cells incubated with tumstatin or tum- labeled according to convention (9). (B and C) The effect of tumstatin peptide statin mutant protein was assessed. **, P Ͻ 0.01, compared with tumstatin (TP) on SCC-PSA1 teratocarcinoma growth. Tumor growth curves show the mutant protein at the same concentration. (Inset) Recombinant production of mean tumor volume Ϯ SEM, n ϭ 13–15. From day 25, the tumstatin peptide- tumstatin and tumstatin mutant protein. Using standard Western blot pro- treated mice were given preimmune serum (PI) or a tumstatin peptide specific- cedure, 500 ng of protein was run in each lane on a 15% acrylamide gel, and antibody (aTP) together with tumstatin peptide, n ϭ 4–5. *, P Ͻ0.05 compared an anti-FLAG antibody was used with anti-mouse IgG linked to horseradish with aTPϩTP; **, P Ͻ 0.01 compared with PBS/DMSO. (D) The importance of peroxidase (Sigma), as primary and secondary antibody, respectively. Lane 1, tumstatin peptide sequence for antiendothelial activity. C-PAE cells were tumstatin mutant; lane 2, tumstatin. (D–F) Tumstatin peptide (TP) binding to incubated with tumstatin peptide or tumstatin peptide mutant and cell endothelial cells preexposed to tumstatin or tumstatin mutant protein. C-PAE proliferation was assessed. *, P Ͻ 0.05 and **, P Ͻ 0.01, compared with cells were incubated with FITC-tumstatin peptide (D), tumstatin (E), or tum- tumstatin peptide mutant at the same concentration. (E) The effect of tum- statin mutant protein (F) before
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