Aldose reductase inhibition suppresses colon cancer cell viability by modulating microRNA-21 mediated programmed cell death 4 (PDCD4) expression.
Aldose reductase inhibition suppresses colon cancer cell viability by modulating microRNA-21 mediated programmed cell death 4 (PDCD4) expression.
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DOI：
10.1016/j.ejca.2013.05.031
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发表时间：
2013-10
影响因子：
8.4
通讯作者：
Srivastava, Satish K.
中科院分区：
文献类型：
--
作者：
Saxena, Ashish;Shoeb, Mohammad;Ramana, Kota V.;Srivastava, Satish K.
抑制多元醇途径酶醛糖还原酶（AR）已被证明可以防止结肠癌细胞在培养物和裸鼠异种移植物中的生长。然而，AR在生长因子诱导的结肠癌细胞生长中的介导作用还不清楚。在这项研究中，我们研究了AR抑制如何通过调节microRNA（miR）-21介导的PDCD 4在体外和体内结肠癌细胞中的表达来防止肿瘤生长。用EGF处理结肠癌细胞（HT 29、SW 480和Caco-2）导致miR-21表达增加，并且抑制AR阻止了其表达。此外，AR抑制还增加了PDCD 4，其是人结肠癌细胞中miR-21的假定靶点。AR的抑制也阻止了EGF诱导的PDCD 4磷酸化。用AR抑制剂非达司他处理HT 29细胞，阻止EGF诱导的mTOR、Raptor、eIF 4 E、S6 K和4 E-BP 1的磷酸化，并增加AMPK的磷酸化。类似地，在裸鼠异种移植组织中，与对照组相比，AR受体处理的小鼠中的PDCD 4和4 E-BP 1水平显著更高。总的来说，这些结果表明AR抑制通过下调miR-21表达并通过ROS/AMPK/mTOR/AP 1/4 E-BP 1途径增加PDCD 4水平来预防生长因子诱导的结肠癌生长。
Inhibition of polyol pathway enzyme aldose reductase (AR) has been shown to prevent colon cancer cells growth in culture and in nude mice xenografts. However, the role of AR in the mediation of growth factor-induced colon cancer cells growth is not well understood. In this study, we have investigated how AR inhibition prevents tumor growth via regulation of microRNA (miR)-21-mediated PDCD4 expression in colon cancer cells in in vitro and in vivo. Treatment of colon cancer cells (HT29, SW480 and Caco-2) with EGF caused increased expression of miR-21 and inhibition of AR prevented it. Further, AR inhibition also increased PDCD4, a putative target of miR-21 in human colon cancer cells. Inhibition of AR also prevented EGF-induced phosphorylation of PDCD4. Treatment of HT29 cells with AR inhibitor, fidarestat, prevented the EGF-induced phosphorylation of mTOR, Raptor, eIF4E, S6K and 4E-BP1 and increased the phosphorylation of AMPK. Similarly, in nude mice xenograft tissues, PDCD4 and 4E-BP1 levels were significantly higher in AR inhibitor-treated mice compared to controls. Collectively, these results indicate that AR inhibition prevents growth factors-induced colon cancer growth by down-regulating miR-21 expression and increasing PDCD4 levels through the ROS/AMPK/mTOR/AP1/4E-BP1 pathway.
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影响因子：
8
作者：
Talotta, F.;Cimmino, A.;Verde, P.
通讯作者：
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影响因子：
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作者：
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通讯作者：
Srivastava, Satish K.
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作者：
Tammali, Ravinder;Reddy, Aramati B. M.;Srivastava, Satish K.
通讯作者：
Srivastava, Satish K.