Excess hepsin proteolytic activity limits oncogenic signaling and induces ER stress and autophagy in prostate cancer cells

The serine protease hepsin is frequently overexpressed in human prostate cancer (PCa) and is associated with matrix degradation and PCa progression in mice. Curiously, low expression of hepsin is associated with poor survival in different cancer types, and transgenic overexpression of hepsin leads t...

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Bibliographic Details
Published in:Cell death & disease 2019-08, Vol.10 (8), p.601, Article 601
Main Authors: Willbold, Ramona, Wirth, Katharina, Martini, Thomas, Sültmann, Holger, Bolenz, Christian, Wittig, Rainer
Format: Article
Language:English
Subjects:
Animals
Autophagy
Autophagy - genetics
Bortezomib
Carcinogenesis - genetics
Cell fate
Cinnamates - pharmacology
Confocal microscopy
Cytoplasm
Deficient mutant
Endoplasmic Reticulum Stress - drug effects
Endoplasmic Reticulum-Associated Degradation - genetics
Gene Expression Regulation, Neoplastic - drug effects
Heterografts
Humans
Macrolides - pharmacology
Male
Mice
Microtubule-Associated Proteins - genetics
Neoplastic Stem Cells - metabolism
Neoplastic Stem Cells - pathology
PC-3 Cells
Phagocytosis
Prostate cancer
Prostatic Neoplasms - genetics
Prostatic Neoplasms - pathology
Proteasomes
Protein folding
Protein transport
Proteins
Proteolysis
Sequestosome-1 Protein - genetics
Serine
Serine Endopeptidases - genetics
Serine proteinase
Surface markers
Thiourea - analogs & derivatives
Thiourea - pharmacology
Tumor cell lines
Tumors
Ubiquitin
Xenografts
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Summary:The serine protease hepsin is frequently overexpressed in human prostate cancer (PCa) and is associated with matrix degradation and PCa progression in mice. Curiously, low expression of hepsin is associated with poor survival in different cancer types, and transgenic overexpression of hepsin leads to loss of viability in various cancer cell lines. Here, by comparing isogenic transfectants of the PCa cell line PC-3 providing inducible overexpression of wild-type hepsin (HPN) vs. the protease-deficient mutant HPN , we were able to attribute hepsin-mediated tumor-adverse effects to its excess proteolytic activity. A stem-like expression signature of surface markers and adhesion molecules, Notch intracellular domain release, and increased pericellular protease activity were associated with low expression levels of wild-type hepsin, but were partially lost in response to overexpression. Instead, overexpression of wild-type hepsin, but not of HPN , induced relocalization of the protein to the cytoplasm, and increased autophagic flux in vitro as well as LC3B punctae frequency in tumor xenografts. Confocal microscopy revealed colocalization of wild-type hepsin with both LC3B punctae as well as with the autophagy cargo receptor p62/SQSTM1. Overexpression of wild type, but not protease-deficient hepsin induced expression and nuclear presence of CHOP, indicating activation of the unfolded protein response and ER-associated protein degradation (ERAD). Whereas inhibitors of ER stress and secretory protein trafficking slightly increased viability, combined inhibition of the ubiquitin-proteasome degradation pathway (by bortezomib) with either ER stress (by salubrinal) or autophagy (by bafilomycin A1) revealed a significant decrease of viability during overexpression of wild-type hepsin in PC-3 cells. Our results demonstrate that a precise control of Hepsin proteolytic activity is critical for PCa cell fate and suggest, that the interference with ERAD could be a promising therapeutic option, leading to induction of proteotoxicity in hepsin-overexpressing tumors.
ISSN:2041-4889
2041-4889
DOI:10.1038/s41419-019-1830-8