Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: EC:3.4.25.1 (
proteasome
)
28,817
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
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
S353A
, 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
S353A
, 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.
...
PMID:Excess hepsin proteolytic activity limits oncogenic signaling and induces ER stress and autophagy in prostate cancer cells. 3205 94
