Aldose reductase deficiency in mice prevents azoxymethane-induced colonic preneoplastic aberrant crypt foci formation
Aldose reductase deficiency in mice prevents azoxymethane-induced colonic preneoplastic aberrant crypt foci formation
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DOI：
10.1093/carcin/bgn246
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发表时间：
2009-05-01
期刊：
影响因子：
4.7
通讯作者：
Srivastava, Satish K.
中科院分区：
文献类型：
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作者：
Tammali, Ravinder;Reddy, Aramati B. M.;Srivastava, Satish K.
醛糖还原酶（AR; EC 1.1.1.21）是一种烟酰胺腺嘌呤二核苷酸磷酸依赖性醛酮还原酶，已显示参与由炎性细胞因子、趋化因子和生长因子引发的氧化应激信号传导。最近，我们已经表明，抑制这种酶可以防止结肠癌细胞在体外以及裸鼠异种移植瘤的生长。本文利用氧化偶氮甲烷（AOM）诱导的小鼠结肠癌模型，研究AR在结肠癌前异常隐窝灶（ACF）形成中的介导作用。给雄性BALB/c小鼠施用不含或含AR抑制剂sorbinil的AOM，并且在方案结束时，将所有小鼠安乐死，并评价结肠的ACF形成。sorbinil的管理显着降低AOM诱导的ACF的数量。同样地，施用AOM的AR-裸小鼠表现出对ACF形成的显著抗性。此外，抑制小鼠AR或敲除小鼠AR基因可显着阻止AOM诱导的诱导型一氧化氮合酶和环氧合酶-2蛋白及其信使RNA的表达。AR抑制或敲低也显著降低了蛋白激酶C（PKC）β 2和核因子κ结合蛋白的磷酸化，以及小鼠结肠中肿瘤前标志物蛋白如细胞周期蛋白D1和β-连环蛋白的表达。我们的研究结果表明，AR介导的ACF在AOM治疗的小鼠，从而抑制AR可以提供一个有效的化学预防方法治疗结肠癌。
Aldose reductase (AR; EC 1.1.1.21), an nicotinamide adenine dinucleotide phosphate-dependent aldo-keto reductase, has been shown to be involved in oxidative stress signaling initiated by inflammatory cytokines, chemokines and growth factors. Recently, we have shown that inhibition of this enzyme prevents the growth of colon cancer cells in vitro as well as in nude mice xenografts. Herein, we investigated the mediation of AR in the formation of colonic preneoplastic aberrant crypt foci (ACF) using azoxymethane (AOM)-induced colon cancer mice model. Male BALB/c mice were administrated with AOM without or with AR inhibitor, sorbinil and at the end of the protocol, all the mice were euthanized and colons were evaluated for ACF formation. Administration of sorbinil significantly lowered the number of AOM-induced ACF. Similarly, AR-null mice administered with AOM demonstrated significant resistance to ACF formation. Furthermore, inhibition of AR or knockout of AR gene in the mice significantly prevented AOM-induced expression of inducible nitric oxide synthase and cyclooxygenase-2 proteins as well as their messenger RNA. AR inhibition or knockdown also significantly decreased the phosphorylation of protein kinase C (PKC) beta 2 and nuclear factor kappa binding protein as well as expression of preneoplastic marker proteins such as cyclin D1 and beta-catenin in mice colons. Our results suggest that AR mediates the formation of ACF in AOM-treated mice and thereby inhibition of AR could provide an effective chemopreventive approach for the treatment of colon cancer.