Aldose reductase inhibitor, fidarestat regulates mitochondrial biogenesis via Nrf2/HO-1/AMPK pathway in colon cancer cells.
Aldose reductase inhibitor, fidarestat regulates mitochondrial biogenesis via Nrf2/HO-1/AMPK pathway in colon cancer cells.
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DOI：
10.1016/j.canlet.2017.09.031
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发表时间：
2017-12-28
期刊：
影响因子：
9.7
通讯作者：
Srivastava SK
中科院分区：
文献类型：
--
作者：
Shukla K;Sonowal H;Saxena A;Ramana KV;Srivastava SK
虽然我们之前已经证明醛糖还原酶（AR）抑制剂在培养物和裸鼠异种移植物中可以阻止结直肠癌细胞（CRC）的生长，但其机制尚不清楚。在这项研究中，我们研究了AR抑制如何通过Nrf2/HO-1途径调节线粒体生物发生来阻止CRC的生长。如SW-480、HT29和HCT116等CRC细胞与AR抑制剂非共价结合的非达司他孵育后，Nrf2的表达增加。此外，非达司他增强了egf诱导的CRC细胞中Nrf-2的表达。非达司他还增加了SW480细胞中Nrf2 -DNA结合活性、HO-1和NQO1的表达以及SOD和过氧化氢酶的活化。同样，在裸鼠异种移植肿瘤组织中，非达司他治疗小鼠的Nrf2和HO-1水平显著高于对照组。此外，在非达司他存在的情况下，EGF刺激CRC细胞增加了PGC-1α、Nrf1和TFAM的mRNA水平以及PGC-1α、TFAM和COX-IV的蛋白水平，并通过8-羟基-2 ' -脱氧鸟苷水平测量降低了线粒体DNA损伤。AR抑制剂还可以调节egf处理细胞中AMPK和mTOR的磷酸化以及p53的表达。总之，我们的研究结果表明，AR抑制剂通过增加Nrf2/HO-1/AMPK/p53的表达和减少线粒体DNA损伤来增加线粒体生物发生，从而阻止CRC的生长。醛糖还原酶抑制剂fidarestat通过上调AMPK/Nrf2/HO-1/PGC-1α信号抑制癌细胞生长。
Although we have shown earlier that aldose reductase (AR) inhibitors prevent colorectal cancer cell (CRC) growth in culture as well as in nude mice xenografts, the mechanism(s) is not well understood. In this study, we have investigated how AR inhibition prevents CRC growth by regulating the mitochondrial biogenesis via Nrf2/HO-1 pathway. Incubation of CRC cells such as SW-480, HT29, and HCT116 with AR inhibitor, fidarestat that non-covalently binds to the enzyme, increases the expression of Nrf2. Further, fidarestat augmented the EGF-induced expression of Nrf-2 in CRC cells. Fidarestat also increased the Nrf2 -DNA binding activity as well as expression of HO-1 and NQO1 and activation of SOD and catalase in SW480 cells. Similarly, in nude mice xenograft tumor tissues, Nrf2 and HO-1 levels were significantly higher in fidarestat-treated mice compared to controls. Further, stimulation of CRC cells with EGF in the presence of fidarestat increased the mRNA levels of PGC-1α, Nrf1 and TFAM and protein levels of PGC-1α, TFAM and COX-IV and decreased the mitochondrial DNA damage as measured by 8-hydroxy-2′-deoxyguanosine levels. AR inhibitor also modulated the phosphorylations of AMPK and mTOR and expression of p53 in EGF-treated cells. Collectively, our results indicate that AR inhibitor prevents CRC growth by increasing mitochondrial biogenesis via increasing the expression of Nrf2/HO-1/AMPK/p53 and decreasing the mitochondrial DNA damage. Aldose reductase inhibitor, fidarestat prevents cancer cell growth by upregulating AMPK/Nrf2/HO-1/PGC-1α signals.
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DOI：
10.1016/j.bbamcr.2010.09.019
发表时间：
2011-07
期刊：
Biochimica et biophysica acta
影响因子：
--
作者：
Scarpulla RC
通讯作者：
Scarpulla RC
DOI：
10.1124/jpet.111.190132
发表时间：
2012-04-01
影响因子：
3.5
作者：
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通讯作者：
Rhodes, Kenneth J.
影响因子：
3
作者：
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通讯作者：
Klampfer L
影响因子：
10.5
作者：
Jaramillo MC;Zhang DD
通讯作者：
Zhang DD
影响因子：
4.1
作者：
Balogun, E;Hoque, M;Motterlini, R
通讯作者：
Motterlini, R