TOXI 40 |
| Aldo-keto reductase (AKR) 1C3 (prostaglandin F synthase) likely contributes to breast cancer through regulation of prostaglandin (PG) signaling. AKR1C3 stereo-specifically reduces PGH2 and PGD2 to form PGF2a and 9a,11b-PGF2. These isomers bind F prostanoid receptors and stimulate cell proliferation, angiogenesis, and invasion. AKR1C3 also prevents the non-enzymatic formation of anti-proliferative PGJ2 products from PGD2. We examined PG metabolism by homogenous recombinant AKR1C3 and by MCF-7 cells that over-express AKR1C3. This was accomplished with a radiometric method using [3H]-PGD2 and separation by TLC and a chiral HPLC/APCI/MS method that utilized pentafluorobenzyl derivatization to provide sensitive, stereoisomer-specific, PG detection. We observed rapid reduction of PGD2 to 11b-PGF2 by recombinant AKR1C3, which completely prevented PGJ2 product formation. Similarly MCF-7 cells expressing AKR1C3 exhibited increased formation of PGF2 isomers and decreased formation of PGJ2 products. AKR1C3 is therefore predicted to contribute to proliferative PG signaling and represents a target for chemoprevention of breast cancer. [Supported by NIH grants T32 DK007314-25 (M.C.B.), R01 CA90744 and P30 ES013508 (T.M.P.)] |
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Poster Session and Awards
6:00 PM-10:00 PM, Tuesday, August 21, 2007 BCEC -- 204 A/B, Poster
Sci-Mix
Division of Chemical Toxicology |