Suppression of prostate tumor cell growth by stromal cell prostaglandin D synthase-derived products.
Stromal-epithelial interactions and the bioactive molecules produced by these interactions maintain tissue homeostasis and influence carcinogenesis. Bioactive prostaglandins produced by prostaglandin synthases and secreted by the prostate into seminal plasma are thought to support reproduction, but their endogenous effects on cancer formation remain unresolved. No studies to date have examined prostaglandin enzyme production or prostaglandin metabolism in normal prostate stromal cells. Our results show that lipocalin-type prostaglandin D synthase (L-PGDS) and prostaglandin D2 (PGD2) metabolites produced by normal prostate stromal cells inhibited tumor cell growth through a peroxisome proliferator-activated receptor gamma (PPARgamma)-dependent mechanism. Enzymatic products of stromal cell L-PGDS included high levels of PGD2 and 15-deoxy-delta(12,14)-PGD2 but low levels of 15-deoxy-delta(12,14)-prostaglandin J2. These PGD2 metabolites activated the PPARgamma ligand-binding domain and the peroxisome proliferator response element reporter systems. Thus, growth suppression of PPARgamma-expressing tumor cells by PGD2 metabolites in the prostate microenvironment is likely to be an endogenous mechanism involved in tumor suppression that potentially contributes to the indolence and long latency period of this disease.
Kim
Jeri
J
Department of Genitourinary Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA.
Yang
Peiying
P
Suraokar
Milind
M
Sabichi
Anita L
AL
Llansa
Norma D
ND
Mendoza
Gabriela
G
Subbarayan
Vemparalla
V
Logothetis
Christopher J
CJ
Newman
Robert A
RA
Lippman
Scott M
SM
Menter
David G
DG
D016718:Arachidonic Acid / Q000378:metabolism; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D019204:GTP-Binding Proteins / Q000378:metabolism; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000096:biosynthesis / Q000378:metabolism*; D054834:Lipocalins; D008297:Male; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D015230:Prostaglandin D2 / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D011971:Receptors, Immunologic / Q000172:deficiency / Q000378:metabolism; D011982:Receptors, Prostaglandin / Q000172:deficiency / Q000378:metabolism; D017154:Stromal Cells / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D015533:Transcriptional Activation
D054834:Lipocalins; D047495:PPAR gamma; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; C501562:prostanoid D receptor 1, human; D016718:Arachidonic Acid; D019204:GTP-Binding Proteins; D019746:Intramolecular Oxidoreductases; C022466:prostaglandin R2 D-isomerase; D015230:Prostaglandin D2; C036293:prostaglandin D2 receptor