Inhibition of DHCR24/seladin-1 impairs cellular homeostasis in prostate cancer.
BACKGROUND
Seladin-1 belongs to a subgroup of androgen-dependent genes associated with anti-proliferative, pro-differentiation, and pro-apoptotic functions and plays a protective role against oncogenic stress. The present study aims to investigate the localization and expression of Seladin-1 protein in normal and tumoral human prostatic tissues as well as to explore its role in proliferation and steroid secretion in androgen-dependent (LnCaP) and androgen-independent (DU145) cell lines and in human prostate primary cell culture.


METHODS
Seladin-1 protein localization and expression were assessed on whole tissue sections by tissue array/immunohistochemistry and following immunofluorescence and Western blotting. Proliferation (Ki67 fluorescence labeling and cell counts) and steroid secretion (ELISA) were assessed in cell lines and primary epithelial cell cultures.


RESULTS
In human prostatic tissue and cells, Seladin-1 was mostly localized within epithelial and rarely within stromal cells and primarily present in secretory luminal cells of normal and tumoral prostate cells. Its expression was increased in low-risk prostate cancer but reduced in advanced prostate cancers when compared to normal tissues. Seladin-1 was highly expressed in LnCaP, whereas its expression level was lower in DU145 cells. Seladin-1 inhibition by treatment with its specific inhibitor, U18666A (75 nM), increased proliferation in LnCaP and primary cell culture, as well as testosterone and dihydrotestosterone levels in both LnCaP and DU145 cell lines.


CONCLUSIONS
Seladin-1 involvement in proliferation and secretion suggests that its downregulation may be a major mechanism causing prostate cancer evolution. Seladin-1 may thus potentially decrease cell growth and steroid dependency in low-grade prostate cancer.
Battista
Marie-Claude
MC
Faculté de Médecine et des Sciences de la Santé, Service of Endocrinology, Université de Sherbrooke, Sherbrooke, Quebec, Canada.
Guimond
Marie-Odile
MO
Roberge
Claude
C
Doueik
Alexandre A
AA
Fazli
Ladan
L
Gleave
Martin
M
Sabbagh
Robert
R
Gallo-Payet
Nicole
N
D000704:Analysis of Variance; D000736:Androstenes / Q000494:pharmacology; D015153:Blotting, Western; D002452:Cell Count; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D015972:Gene Expression Regulation, Neoplastic; D006706:Homeostasis / Q000187:drug effects*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D011467:Prostate / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000378:metabolism*; D046888:Tissue Array Analysis
D000736:Androstenes; D004791:Enzyme Inhibitors; D009419:Nerve Tissue Proteins; C006261:3-beta-(2-(diethylamino)ethoxy)androst-5-en-17-one; D044925:Oxidoreductases Acting on CH-CH Group Donors; C499055:DHCR24 protein, human