AKR1C2 and AKR1C3 mediated prostaglandin D-2 metabolism augments the P13K/Akt proliferative signaling pathway in human prostate cancer cells
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 PGD(2) to 9 alpha. 11 beta-PGF(2 alpha)., whereas AKR1C2-mediated PG metabolism remains unclear. The accumulation of PGF(2 alpha). 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 PGD(2) conversion in human prostatecell 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 PGD(2)-stimulated PC-3 cell proliferation in these stable transfectants. In addition, PGD2 significantly elevated levels of total Akt protein expression and Akt Ser(473) phosphorylation in AKR1C2 and AKR1C3 stable transfectants; and inclusion of a phosphatidylinositol 3-kinase (PI3K) chemical inhibitor (LY294002) attenuated PGD(2)-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. Published by Elsevier Ireland Ltd.
Wang, S., Yang, Q., Fung, K-M., & Lin, H-K. (2008). AKR1C2 and AKR1C3 mediated prostaglandin D-2 metabolism augments the P13K/Akt proliferative signaling pathway in human prostate cancer cells. Molecular and Cellular Endocrinology, 289(1-2), 60-66. https://doi.org/10.1016/j.mce.2008.04.004