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GRP78 up-regulation is associated with androgen receptor status, Hsp70-Hsp90 client proteins and castrate-resistant prostate cancer
The Journal of pathology, 2011, Vol.223 (1), p.81-87
Tan, Shaun S
Ahmad, Imran
Bennett, Haley L
Singh, Lukram
Nixon, Colin
Seywright, Morag
Barnetson, Robert J
Edwards, Joanne
Leung, Hing Y
2011
Volltextzugriff (PDF)
Details
Autor(en) / Beteiligte
Tan, Shaun S
Ahmad, Imran
Bennett, Haley L
Singh, Lukram
Nixon, Colin
Seywright, Morag
Barnetson, Robert J
Edwards, Joanne
Leung, Hing Y
Titel
GRP78 up-regulation is associated with androgen receptor status, Hsp70-Hsp90 client proteins and castrate-resistant prostate cancer
Ist Teil von
The Journal of pathology, 2011, Vol.223 (1), p.81-87
Ort / Verlag
Chichester, UK: John Wiley & Sons, Ltd
Erscheinungsjahr
2011
Quelle
Wiley-Blackwell Journals
Beschreibungen/Notizen
GRP78/BiP is a key member of the molecular chaperone heat shock protein (Hsp) 70 family. It has a critical role in prostate cancer (PC) including Pten loss-driven carcinogenesis, but the molecular basis of this remains unclear. We investigated the effect of GRP78 and its putative client proteins, including androgen receptor (AR) in clinical PC. Expression of GRP78 and key Hsp70-hsp90 client proteins (HER2, HER3, AR and AKT) were studied in an incidence tissue microarray (TMA) of prostate cancer. The relationship of GRP78 and AR was further tested in in vitro cell models (LNCaP and its derived LNCaP-CR subclone) and a matched TMA of hormone-naïve (HNPC) and castrate-resistant prostate cancer (CRPC). In vitro and in vivo expression of GRP78 and client proteins were assessed by western blotting and immunohistochemistry, respectively, using the weighted histoscore method. Significant co-expression of GRP78, pAKT, HER2, HER3 and AR was observed in PC. Abnormal AR, GRP78 and pAKT expression have significant impact on patient survival. GRP78 expression in AR⁺ tumours was significantly higher than in AR⁻ tumours. In keeping with our clinical data, activation of AR by dihydrotestosterone (DHT) potently activated GRP78 expression in both LNCaP and LNCaP-CR cells. For the first time, using a matched HNPC and CRPC TMA, enhanced cytoplasmic and membranous GRP78 expression was observed in CRPC. Future prospective studies are therefore warranted to validate GRP78 as prognostic marker and therapeutic target, in the context of the AR and pAKT status. In summary, GRP78 is co-expressed with Hsp70-hsp90 client proteins. Up-regulated expression of AR and GRP78 expression in untreated prostate cancer predicts a less favourable outcome. This points to the importance of understanding in the molecular interaction among AR, GRP78 and AKT. Copyright © 2010 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Sprache
Englisch
Identifikatoren
ISSN: 0022-3417
eISSN: 1096-9896
DOI: 10.1002/path.2795
Titel-ID: cdi_crossref_primary_10_1002_path_2795
Format
–
Schlagworte
androgen receptor
,
Biological and medical sciences
,
Biomarkers, Tumor - metabolism
,
castrate-resistant prostate cancer
,
Disease Progression
,
Gene Expression Regulation, Neoplastic
,
GRP78
,
heat shock protein
,
Heat-Shock Proteins - biosynthesis
,
Heat-Shock Proteins - genetics
,
Heat-Shock Proteins - metabolism
,
Humans
,
Investigative techniques, diagnostic techniques (general aspects)
,
Male
,
Medical sciences
,
Neoplasm Proteins - metabolism
,
Nephrology. Urinary tract diseases
,
Orchiectomy
,
Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques
,
Prostatic Neoplasms - metabolism
,
Prostatic Neoplasms - surgery
,
Receptors, Androgen - metabolism
,
Survival Analysis
,
Tumor Cells, Cultured
,
Tumors of the urinary system
,
Up-Regulation
,
Urinary tract. Prostate gland
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