Inhibition of TMPRSS2 by HAI-2 reduces prostate cancer cell invasion and metastasis
Journal
Oncogene
Journal Volume
39
Journal Issue
37
Pages
5950
Date Issued
2020
Author(s)
Hsu, Ting-Wei
Wu, Shang-Ru
Lan, Shao-Wei
Hsiao, Ting-Feng
Lin, Hsin-Ying
Lin, Hsin-Hsien
Tu, Hsin-Fang
Lee, Cheng-Fan
Huang, Cheng-Chung
Chen, Mei-Ju May
Hsiao, Pei-Wen
Abstract
TMPRSS2 is an important membrane-anchored serine protease involved in human prostate cancer progression and metastasis. A serine protease physiologically often comes together with a cognate inhibitor for execution of proteolytically biologic function; however, TMPRSS2's cognate inhibitor is still elusive. To identify the cognate inhibitor of TMPRSS2, in this study, we applied co-immunoprecipitation and LC/MS/MS analysis and isolated hepatocyte growth factor activator inhibitors (HAIs) to be potential inhibitor candidates for TMPRSS2. Moreover, the recombinant HAI-2 proteins exhibited a better inhibitory effect on TMPRSS2 proteolytic activity than HAI-1, and recombinant HAI-2 proteins had a high affinity to form a complex with TMPRSS2. The immunofluorescence images further showed that TMPRSS2 was co-localized to HAI-2. Both KD1 and KD2 domain of HAI-2 showed comparable inhibitory effects on TMPRSS2 proteolytic activity. In addition, HAI-2 overexpression could suppress the induction effect of TMPRSS2 on pro-HGF activation, extracellular matrix degradation and prostate cancer cell invasion. We further determined that the expression levels of TMPRSS2 were inversely correlated with HAI-2 levels during prostate cancer progression. In orthotopic xenograft animal model, TMPRSS2 overexpression promoted prostate cancer metastasis, and HAI-2 overexpression efficiently blocked TMPRSS2-induced metastasis. In summary, the results together indicate that HAI-2 can function as a cognate inhibitor for TMPRSS2 in human prostate cancer cells and may serve as a potential factor to suppress TMPRSS2-mediated malignancy.
SDGs
Other Subjects
carrier proteins and binding proteins; hepatocyte growth factor activator inhibitor 1; hepatocyte growth factor activator inhibitor 2; recombinant protein; serine proteinase; transmembrane serine protease 2; unclassified drug; carrier protein; leukocyte elastase inhibitor; membrane protein; protein binding; serine proteinase; SPINT1 protein, human; SPINT2 protein, human; TMPRSS2 protein, human; Article; binding affinity; cancer growth; controlled study; enzyme inhibition; extracellular matrix; human; human cell; immunoprecipitation; liquid chromatography-mass spectrometry; metastasis; priority journal; prostate cancer cell line; protein binding; protein degradation; protein domain; protein expression; protein protein interaction; tumor growth; tumor invasion; animal; chemistry; disease model; male; metabolism; pathology; prostate tumor; protein analysis; tumor cell line; tumor invasion; xenograft; Animals; Carrier Proteins; Cell Line, Tumor; Disease Models, Animal; Heterografts; Humans; Male; Membrane Glycoproteins; Neoplasm Invasiveness; Prostatic Neoplasms; Protein Binding; Protein Interaction Domains and Motifs; Protein Interaction Mapping; Proteinase Inhibitory Proteins, Secretory; Proteolysis; Serine Endopeptidases
Publisher
SPRINGERNATURE
Type
journal article