Aldose Reductase Inhibition Prevents Hypoxia-induced Increase in Hypoxia-inducible Factor-1α (HIF-1α) and Vascular Endothelial Growth Factor (VEGF) by Regulating 26 S Proteasome-mediated Protein Degradation in Human Colon Cancer Cells (Publication with Expression of Concern. See vol. 294, pg. 1634, 2019)
Aldose Reductase Inhibition Prevents Hypoxia-induced Increase in Hypoxia-inducible Factor-1α (HIF-1α) and Vascular Endothelial Growth Factor (VEGF) by Regulating 26 S Proteasome-mediated Protein Degradation in Human Colon Cancer Cells (Publication with Expression of Concern. See vol. 294, pg. 1634, 2019)
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DOI：
10.1074/jbc.m111.219733
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发表时间：
2011-07-08
影响因子：
4.8
通讯作者：
Ramana, Kota V.
中科院分区：
文献类型：
--
作者：
Tammali, Ravinder;Saxena, Ashish;Ramana, Kota V.
瘤内缺氧的发展是快速进展的实体瘤的标志，使肿瘤细胞对化疗和放疗产生耐药性。我们最近的研究表明，醛糖还原酶（AR）是一种催化脂质醛及其谷胱甘肽偶联物还原的酶，通过抑制nf - κ b依赖的氧化应激介导的炎症和致癌标志物的激活，可以在培养和裸鼠异种移植物中阻止人类结肠癌细胞的生长。然而，AR在介导缺氧应激信号中的作用尚不清楚。因此，我们研究了AR抑制缺氧诱导的人结肠癌细胞生长和侵袭的分子机制。我们的研究结果表明，药物抑制剂非达司他抑制AR或AR特异性siRNA消融可阻止缺氧诱导的HT29、SW480和Caco-2结肠癌细胞的增殖。此外，缺氧诱导的结肠癌细胞中HIF-1 α水平的升高被AR抑制显著降低。在缺氧条件下，用AR抑制剂非达司他（fidarestat）处理HT29细胞可显著降低血管内皮生长因子（HIF-1 α的下调靶点）mRNA和蛋白水平的表达，并阻止PI3K/AKT、GSK3 β、Snail和赖氨酸氧化酶的激活。此外，在26 S蛋白酶体的有效抑制剂MG132的存在下，AR抑制对缺氧诱导的HIF-1 α蛋白积累的抑制被消除。此外，AR抑制还抑制了缺氧诱导的炎症分子Cox-2、PGE2以及细胞外基质蛋白MMP2、vimentin、uPAR、赖氨酸氧化酶2的表达。总之，我们的研究结果表明，AR介导缺氧信号，导致肿瘤进展和侵袭。
The development of intratumoral hypoxia, a hallmark of rapidly progressing solid tumors, renders tumor cells resistant to chemotherapy and radiation therapy. We have recently shown that inhibition of aldose reductase (AR), an enzyme that catalyzes the reduction of lipid aldehydes and their glutathione conjugates, prevents human colon cancer cell growth in culture as well as in nude mouse xenografts by inhibiting the NF-kappa B-dependent activation of oxidative stress-mediated inflammatory and carcinogenic markers. However, the role of AR in mediating hypoxic stress signals is not known. We therefore investigated the molecular mechanisms by which AR inhibition prevents the hypoxia-inducedhumancolon cancer cells growth and invasion. Our results indicate that AR inhibition by the pharmacological inhibitor fidarestat or ablation by AR-specific siRNA prevents hypoxia-induced proliferation of HT29, SW480, and Caco-2 colon cancer cells. Furthermore, hypoxia-induced increase in the level of HIF-1 alpha in colon cancer cells was significantly decreased by AR inhibition. During hypoxic conditions, treatment of HT29 cells with the AR inhibitor fidarestat significantly decreased the expression of vascular endothelial growth factor, a down target of HIF-1 alpha, at both mRNA and protein levels and also prevented the activation of PI3K/AKT, GSK3 beta, Snail, and lysyl oxidase. Furthermore, inhibition of hypoxia-induced HIF-1 alpha protein accumulation by AR inhibition was abolished in the presence of MG132, a potent inhibitor of the 26 S proteasome. In addition, AR inhibition also prevented the hypoxia-induced inflammatory molecules such as Cox-2 and PGE2 and expression of extracellular matrix proteins such as MMP2, vimentin, uPAR, and lysyl oxidase 2. In conclusion, our results indicate that AR mediates hypoxic signals, leading to tumor progression and invasion.