AKR1C2 and AKR1C3 mediated prostaglandin D2 metabolism augments the PI3K/Akt proliferative signaling pathway in human prostate cancer cells.

Abstract

Members of the aldo-keto reductase (AKR) superfamily have been implicated in prostaglandin (PG) metabolism and prostate cancer. AKR1C3 possesses 11-ketoprostaglandin reductase activity and is capable of converting PGD2 to 9alpha, 11beta-PGF2alpha, whereas AKR1C2-mediated PG metabolism remains unclear. The accumulation of PGF2alpha may generate proliferative signals to promote prostate cell growth. Levels of AKR1C2 and AKR1C3 expression are elevated in localized and advanced prostate cancer. To study the significance of AKR1C2- and AKR1C3-mediated PGD2 conversion in human prostate cell proliferation, we stably transfected androgen insensitive human prostate cancer PC-3 cells with AKR1C2 or AKR1C3 cDNA. PC-3 cells overexpressing AKR1C2 and AKR1C3 had elevated cell proliferation in response to PGD2 stimulation as compared to mock transfectants. Overexpression of AKR1C2 or AKR1C3 did not alter levels of PGF receptor (FP) expression. Inclusion of an FP antagonist (AL8810) significantly suppressed PGD2-stimulated PC-3 cell proliferation in these stable transfectants. In addition, PGD2 significantly elevated levels of total Akt protein expression and Akt Ser473 phosphorylation in AKR1C2 and AKR1C3 stable transfectants; and inclusion of a phosphatidylinositol 3-kinase (PI3K) chemical inhibitor (LY294002) attenuated PGD2-stimulated cell proliferation in these transfectants. Our results suggested that both AKR1C2 and AKR1C3 mediate similar PGD2 conversion toward the accumulation of proliferative signals through FP and PI3K/Akt signaling pathways to promote prostate cell proliferation.

• Authors: Shaobin Wang, Qing Yang, Kar-Ming Fung, Hsueh-Kung Lin
• Journal: Molecular and cellular endocrinology (Mol Cell Endocrinol) Vol. 289 Issue 1-2 Pg. 60-6 (Jul 16 2008) ISSN: 0303-7207 [Print] Ireland
• PMID: 18508192 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• AL 8810 ethylamide
• Chromones
• Morpholines
• Phosphoinositide-3 Kinase Inhibitors
• Receptors, Prostaglandin
• prostaglandin F2alpha receptor
• 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
• Dinoprost
• 3-Hydroxysteroid Dehydrogenases
• Hydroxysteroid Dehydrogenases
• Hydroxyprostaglandin Dehydrogenases
• AKR1C2 protein, human
• AKR1C3 protein, human
• Aldo-Keto Reductase Family 1 Member C3
• Proto-Oncogene Proteins c-akt
• Prostaglandin D2

Topics

• 3-Hydroxysteroid Dehydrogenases (genetics, metabolism)
• Aldo-Keto Reductase Family 1 Member C3
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Chromones (pharmacology)
• Dinoprost (analogs & derivatives, pharmacology)
• Humans
• Hydroxyprostaglandin Dehydrogenases (genetics, metabolism)
• Hydroxysteroid Dehydrogenases (genetics, metabolism)
• Male
• Morpholines (pharmacology)
• Phosphatidylinositol 3-Kinases (metabolism)
• Phosphoinositide-3 Kinase Inhibitors
• Prostaglandin D2 (metabolism, pharmacology)
• Prostatic Neoplasms (metabolism, pathology)
• Proto-Oncogene Proteins c-akt (metabolism)
• Receptors, Prostaglandin (metabolism)
• Signal Transduction
• Transfection