Abstract 3873: MMP9 processing of HSBP1 regulates tumor metastases.

Abstract

Abstract Matrix metalloproteinases regulate pathophysiological events by processing matrix proteins and secreted proteins. Previously, we demonstrated that soluble heat shock protein B1 (HSPB1) is released primarily from endothelial cells (ECs) and regulates angiogenesis via direct interaction with vascular endothelial growth factor (VEGF). Here we report that MMP9 can cleave HSPB1 and release anti-angiogenic fragments, which play a key role in tumor metastasis. We mapped the cleavage sites and explored their physiological relevance during these processing events. HSPB1 cleavage by MMP9 inhibited VEGF-induced ECs activation and the C-terminal HSPB1 fragment exhibited more interaction with VEGF than did full-length HSPB1. HSPB1 cleavage occurs during B16F10 lung metastases in wild-type mice and is decreased in B16F10 lung metastases of MMP9-null mice. Finally, we confirmed that secretion of C-terminal HSPB1 fragment was significantly inhibited lung metastases of B6F10 melanoma cells, compared to full-length HSPB1. These data suggest that in vivo MMP9-mediated processing of HSPB1 acts to maintain an angiogenic balance against tumor metastases. Moreover, these findings potentially explain an anti-target effect for the failure of MMP inhibitors in clinical trials, suggesting that MMP inhibitors may have pro-tumorigenic effects by reducing HSPB1 fragmentation. Citation Format: Seo-Hyun Choi, Hae-June Lee, Yeung Bae Jin, Minyoung Lee, Joon Kim, Sam S. Yoon, Yun-Sil Lee, Yoon-Jin Lee. MMP9 processing of HSBP1 regulates tumor metastases. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3873. doi:10.1158/1538-7445.AM2013-3873