MMP9 processing of HSPB1 regulates tumor progression.
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 tumorprogression. 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 progression in wild-type mice. Also, intact HSPB1 was more detected on tumor endothelium of MMP9 null mice than wild type mice. Finally, we confirmed that secretion of C-terminal HSPB1 fragment was significantly inhibited lung and liver tumor progression of B16F10 melanoma cells and lung tumor progression of CT26 colon carcinoma cells, compared to full-length HSPB1. These data suggest that in vivo MMP9-mediated processing of HSPB1 acts to regulate VEGF-induced ECs activation for tumor progression, releasing anti-angiogenic HSPB1 fragments. 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.
Division of Radiation Effects, Korea Institute of Radiological & Medical Sciences, Seoul, Korea ; School of Life Sciences and Biotechnology, Korea University, Seoul, Korea.
Seo-hyun
SH
Choi
Division of Radiation Effects, Korea Institute of Radiological & Medical Sciences, Seoul, Korea.
Hae-June
HJ
Lee
Division of Radiation Effects, Korea Institute of Radiological & Medical Sciences, Seoul, Korea.
Yeung Bae
YB
Jin
Division of Radiation Effects, Korea Institute of Radiological & Medical Sciences, Seoul, Korea.
Junho
J
Jang
College of Pharmacy & Division of Life and Pharmaceutical Sciences, Ewha Womans University, Seoul, Korea.
Ga-young
GY
Kang
Division of Radiation Effects, Korea Institute of Radiological & Medical Sciences, Seoul, Korea.
Minyoung
M
Lee
Laboratory of Tissue Engineering, Korea Institute of Radiological & Medical Sciences, Seoul, Korea.
Chun-Ho
CH
Kim
School of Life Sciences and Biotechnology, Korea University, Seoul, Korea.
Joon
J
Kim
Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.
Sam S
SS
Yoon
College of Pharmacy & Division of Life and Pharmaceutical Sciences, Ewha Womans University, Seoul, Korea.
Yun-sil
YS
Lee
Division of Radiation Effects, Korea Institute of Radiological & Medical Sciences, Seoul, Korea.
Yoon-Jin
YJ
Lee
D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002465:Cell Movement; D049109:Cell Proliferation; D018450:Disease Progression; D042783:Endothelial Cells / Q000378:metabolism; D055551:HSP27 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006360:Heat-Shock Proteins; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018832:Molecular Chaperones; D010766:Phosphorylation; D040262:Receptors, Vascular Endothelial Growth Factor / Q000235:genetics / Q000378:metabolism*; D012509:Sarcoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D012983:Soft Tissue Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology
D055551:HSP27 Heat-Shock Proteins; C057725:HSPB1 protein, human; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D040262:Receptors, Vascular Endothelial Growth Factor; D020780:Matrix Metalloproteinase 9