Aldo-keto reductase 1C3 expression in MCF-7 cells reveals roles in steroid hormone and prostaglandin metabolism that may explain its over-expression in breast cancer.
Aldo-keto reductase 1C3 expression in MCF-7 cells reveals roles in steroid hormone and prostaglandin metabolism that may explain its over-expression in breast cancer.
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DOI：
10.1016/j.jsbmb.2009.12.009
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发表时间：
2010-02-15
影响因子：
4.1
通讯作者：
Penning, Trevor M.
中科院分区：
文献类型：
--
作者：
Byrns, Michael C.;Duan, Ling;Lee, Seon Hwa;Blair, Ian A.;Penning, Trevor M.
关键词：
醛酮还原酶(AKR)1C3(5型17β-羟基类固醇脱氢酶和前列腺素F合成酶)可能通过类固醇激素和前列腺素(PG)代谢促进乳腺的增殖。纯化的重组AKR1C3使PgD2还原为9α，11β-PgF2，Δ4-雄烯二酮还原为睾酮，孕酮还原为20α-羟孕酮，雌酮少量还原为17β-雌二醇。我们建立了稳定表达AKR1C3的MCF-7细胞(MCF-7-AKR1C3细胞)，以模拟其在乳腺癌中的过表达。AKR1C3的表达增加了MCF-7细胞的类固醇转化，导致了促雌激素状态。出乎意料的是，与其他底物相比，在0.1um时，MCF-7-AKR1C3细胞的雌酮还原速度最快。在雌酮和17β-雌二醇作用下，McF-7-AKR1C3细胞的增殖速度是亲代细胞的3倍。因此，AKR1C3是抑制雌激素受体α诱导的增殖的潜在靶点。Mcf-7-AKR1C3细胞还减少了PGD2，限制了其脱水形成PGJ2产物。AKR1C3产物经鉴定为9α，11β-PgF2，并用立体特异性稳定同位素稀释液相色谱质谱联用法进行定量。这种方法将允许检查AKR1C3在内源性前列腺素形成中的作用，以响应炎症刺激。AKR1C3的表达降低了PGD2对MCF-7细胞增殖的抑制作用，提示AKR1C3通过减少15-脱氧-前列腺素J2(15-deoxy-γ，12，14-PGJ2，15dPGJ2)的形成而限制了过氧化物酶体增殖物激活受体γ信号转导通路。
Aldo-keto reductase (AKR) 1C3 (type 5 17β-hydroxysteroid dehydrogenase and prostaglandin F synthase), may stimulate proliferation via steroid hormone and prostaglandin (PG) metabolism in the breast. Purified recombinant AKR1C3 reduces PGD2 to 9α,11β-PGF2, Δ4-androstenedione to testosterone, progesterone to 20α-hydroxyprogesterone, and to a lesser extent, estrone to 17β-estradiol. We established MCF-7 cells that stably express AKR1C3 (MCF-7-AKR1C3 cells) to model its overexpression in breast cancer. AKR1C3 expression increased steroid conversion by MCF-7 cells, leading to a pro-estrogenic state. Unexpectedly, estrone was reduced fastest by MCF-7-AKR1C3 cells when compared to other substrates at 0.1 uM. MCF-7-AKR1C3 cells proliferated three times faster than parental cells in response to estrone and 17β-estradiol. AKR1C3 therefore represents a potential target for attenuating estrogen receptor α induced proliferation. MCF-7-AKR1C3 cells also reduced PGD2, limiting its dehydration to form PGJ2 products. The AKR1C3 product was confirmed as 9α,11β-PGF2 and quantified with a stereospecific stable isotope dilution liquid chromatography-mass spectrometry method. This method will allow the examination of the role of AKR1C3 in endogenous prostaglandin formation in response to inflammatory stimuli. Expression of AKR1C3 reduced the anti-proliferative effects of PGD2 on MCF-7 cells, suggesting that AKR1C3 limits peroxisome proliferator activated receptor γ (PPARγ) signaling by reducing formation of 15-deoxy-Δ12,14-PGJ2 (15dPGJ2).
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