Expression of two WFDC1/ps20 isoforms in prostate stromal cells induces paracrine apoptosis through regulation of PTGS2/COX-2.
WFDC1/Prostate stromal 20 (ps20) is a small secreted protein highly expressed within the prostate stroma. WFDC1/ps20 expression is frequently downregulated or lost in prostate cancer (PCa) and ps20 has demonstrated growth-suppressive functions in numerous tumour model systems, although the mechanisms of this phenomenon are not understood.



Ps20 was cloned and overexpressed in DU145, PC3, LNCaP and WPMY-1 cells. Cellular growth, cell cycle and apoptosis were characterised. WPMY-1 stromal cells expressing ps20 were characterised by transcriptome microarray and the function of WPMY-1 conditioned media on growth of PCa cell lines was assessed.



Prostrate stromal 20 expression enhanced the proliferation of LNCaP cells, whereas stromal WPMY-1 cells were inhibited and underwent increased apoptosis. Prostrate stromal 20-expressing WPMY-1 cells secrete a potently proapoptotic conditioned media. Prostrate stromal 20 overexpression upregulates expression of cyclooxygenase-2 (COX-2) in LNCaP and WPMY-1 cells, and induces expression of a growth-suppressive phenotype, which inhibits proliferation of PCa cells by ps20-expressing WPMY-1 conditioned media. This growth suppression was subsequently shown to be dependent on COX-2 function.



This work posits that expression of ps20 in the prostate stroma can regulate growth of epithelial and other tissues through the prostaglandin synthase pathway, and thereby restricts development and progression of neoplasms. This provides a rational for selective pressure against ps20 expression in tumour- associated stroma.
Department of Infectious Disease, King's College London, Guys Hospital, Great Maze Pond, London SE1 9RT, UK.
Oliver J
OJ
Hickman
Division of Transplantation, King's College London, Guys Hospital, Great Maze Pond, London SE1 9RT, UK.
Richard A
RA
Smith
Division of Transplantation, King's College London, Guys Hospital, Great Maze Pond, London SE1 9RT, UK.
Prokar
P
Dasgupta
Genotypic Technology Pvt Ltd, Bangalore 560094, India.
Sudha Narayana
SN
Rao
Centre for Infectious Disease Research, Indian Institute of Science, Raman Avenue, Bangalore 560012, India.|Institute of Bioinformatics and Biotechnology, Biotech Park, Electronics City Phase I, Bengaluru 560 100, India.
Soumya
S
Nayak
Centre for Infectious Disease Research, Indian Institute of Science, Raman Avenue, Bangalore 560012, India.
Shubha
S
Sreenivasan
Department of Infectious Disease, King's College London, Guys Hospital, Great Maze Pond, London SE1 9RT, UK.|Centre for Infectious Disease Research, Indian Institute of Science, Raman Avenue, Bangalore 560012, India.
Annapurna
A
Vyakarnam
Division of Transplantation, King's College London, Guys Hospital, Great Maze Pond, London SE1 9RT, UK.
Christine
C
Galustian
D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D017077:Culture Media, Conditioned / Q000494:pharmacology; D051546:Cyclooxygenase 2 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D004790:Enzyme Induction / Q000235:genetics; D005109:Extracellular Matrix / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D009363:Neoplasm Proteins / Q000235:genetics / Q000502:physiology*; D019899:Paracrine Communication; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D020033:Protein Isoforms / Q000502:physiology; D011506:Proteins / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D017154:Stromal Cells / Q000378:metabolism*; D059016:Tumor Microenvironment
D017077:Culture Media, Conditioned; D009363:Neoplasm Proteins; D020033:Protein Isoforms; D011506:Proteins; D011993:Recombinant Fusion Proteins; C484310:WFDC1 protein, human; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human