Aldose reductase regulates growth factor-induced cyclooxygenase-2 expression and prostaglandin E2 production in human colon cancer cells
Aldose reductase regulates growth factor-induced cyclooxygenase-2 expression and prostaglandin E2 production in human colon cancer cells
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DOI：
10.1158/0008-5472.can-06-2105
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发表时间：
2006-10-01
期刊：
影响因子：
11.2
通讯作者：
Srivastava, Satish K.
中科院分区：
文献类型：
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作者：
Tammali, Ravinder;Ramana, Kota V.;Srivastava, Satish K.
非甾体抗炎药抑制前列腺素E-2（PGE（2））和环氧合酶（考克斯）-2可减缓结肠癌的进展。抑制醛糖还原酶（AR; EC. 1.1.1.21.）通过sorbinil或通过反义消融阻止人结肠癌细胞Caco-2中成纤维细胞生长因子诱导的和血小板衍生生长因子诱导的PGE（2）合成上调。AR除了还原醛糖外，还有效地还原有毒脂质醛及其与谷胱甘肽的缀合物。抑制AR可阻止生长因子诱导的考克斯-2活性、蛋白质和mRNA，并显著降低核因子-κ B和蛋白激酶C（PKC）的活化、PKG-β 2的磷酸化以及Caco-2细胞生长的进展，但对COVI活性无影响。细胞周期分析表明，抑制AR阻止生长因子诱导的Caco-2细胞增殖在S期。用含量最高、毒性最大的脂质醛4-羟基-反式-2-壬烯醛（HNE）或其谷胱甘肽共轭物[谷胱甘肽-HNE（GS-HNE）]或GS-HNE的AR催化产物谷胱甘肽-1，4-二羟基壬烷（GS-DHN）处理Caco-2细胞，可导致考克斯-2表达和PGE（2）产生增加。抑制AR可阻止HNE或GS-HNE诱导的考克斯-2和PGE上调，但不能阻止GS-DHN诱导的上调（2）。更重要的是，体内研究表明，AR-小干扰RNA（siRNA），而不是对照siRNA，给荷有SW 480人结肠腺癌细胞的裸鼠完全阻止了肿瘤的进展。总的来说，这些观察结果表明，AR是生长因子诱导的考克斯-2、PGE（2）上调和Caco-2细胞生长的强制性介质，表明抑制AR可能是预防结肠癌进展的新治疗方法。
Inhibition of prostaglandin E-2 (PGE(2)) and cyclooxygenase (COX)-2 by nonsteroidal anti-inflammatory drugs reduces the progression of colon cancer. Inhibition of aldose reductase (AR; EC. 1.1.1.21.) by sorbinil or by antisense ablation prevented fibroblast growth factor-induced and platelet-derived growth factor-induced up-regulation of PGE(2) synthesis in human colon cancer cells, Caco-2. AR besides reducing aldo-sugars efficiently reduces toxic lipid aldehydes and their conjugates with glutathione. Inhibition of AR prevented growth factor-induced COX-2 activity, protein, and mRNA and significantly decreased activation of nuclear factor-kappa B and protein kinase C (PKC) and phosphorylation of PKG-beta 2 as well as progression of Caco-2 cell growth but had no effect on COVI activity. Cell cycle analysis suggests that inhibition of AR prevents growth factor-induced proliferation of Caco-2 cells at S phase. Treatment of Caco-2 cells with the most abundant and toxic lipid aldehyde 4-hydroxy-trans-2-nonenal (HNE) or its glutathione-conjugate [glutathionyl-HNE (GS-HNE)] or AR-catalyzed product of GS-HNE, glutathionyl-1,4-dihydroxynonane (GS-DHN), resulted in increased COX-2 expression and PGE(2) production. Inhibition of AR prevented HNE- or GS-HNE-induced but not GS-DHN-induced up-regulation of COX-2 and PGE(2). More importantly, in vivo studies showed that administration of AR-small interfering RNA (siRNA), but not control siRNA, to nude mice bearing SW480 human colon adenocarcinoma cells completely arrested tumor progression. Collectively, these observations suggest that AR is an obligatory mediator of growth factor-induced up-regoulation of COX-2, PGE(2), and growth of Caco-2 cells, indicating that inhibition of AR may be a novel therapeutic approach in preventing the progression of colon cancer.