Natural Product-Derived Antitumor Compound Phenethyl Isothiocyanate Inhibits mTORC1 Activity via TSC2
Natural Product-Derived Antitumor Compound Phenethyl Isothiocyanate Inhibits mTORC1 Activity via TSC2
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DOI：
10.1021/np300049b
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发表时间：
2012-06-01
影响因子：
5.1
通讯作者：
Packham, Graham
中科院分区：
文献类型：
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作者：
Cavell, Breeze E.;Alwi, Sharifah S. Syed;Packham, Graham
异硫氰酸苯乙酯(1)是一种天然的饲料植物化学物质，具有细胞抑制、细胞毒性和抗肿瘤活性。研究了I对mTOR活性的影响，mTOR是一种能够增强许多编码对癌细胞生长至关重要的蛋白质的RNA的翻译，包括血管生成调节因子HIF1α。化合物I有效地阻断了MCF7乳腺癌细胞中HIF1αRNA的翻译，这与4E-BPI和p70 S6K的磷酸化减少有关，这两种底物是含有mTOR的mTORC1复合体的下游底物。化合物1对小鼠胚胎成纤维细胞(MEF)mTORC1活性也有抑制作用。1介导的mTORC1活性抑制似乎不依赖于上游调控因子PTEN、AKT、ERK1/2和AMPK。相反，1介导的mTORC1活性抑制依赖于TSC2的存在，TSC2是负向调节mTORC1活性的复合体的一部分。TSC2基因缺失的MEF对1介导的p70S6K磷酸化抑制具有抵抗力。缺乏TSC2的MEF对1介导的生长抑制也有部分抗性。总体而言，本结果证实了I抑制mTORC1的活性。这取决于TSC2的存在，而mTORC1的抑制有助于1诱导的最佳生长抑制。抑制RNA翻译可能是异硫氰酸苯乙酯抗肿瘤作用的重要组成部分。
Phenethyl isothiocyanate (1) is a natural dietary phytochemical with cytostatic, cytotoxic, and antitumor activity. The effects of I were investigated on the activity of mTOR, a kinase that enhances the translation of many RNAs encoding proteins critical for cancer cell growth, including the angiogenesis regulator HIF1 alpha. Compound I effectively blocked HIF1 alpha RNA translation in MCF7 breast cancer cells, and this was associated with reduced phosphorylation of 4E-BPI and p70 S6K, well-characterized downstream substrates of the mTOR-containing mTORC1 complex. Compound 1 also inhibited mTORC1 activity in mouse embryonic fibroblasts (MEFs). The 1-mediated inhibition of mTORC1 activity appeared to be independent of the upstream regulators PTEN, AKT, ERK1/2, and AMPK. By contrast, 1-mediated inhibition of mTORC1 activity was dependent on the presence of TSC2, part of a complex that regulates mTORC1 activity negatively. TSC2-deficient MEFs were resistant to 1-mediated inhibition of p70 S6K phosphorylation. TSC2-deficient MEFs were also partially resistant to 1-mediated growth inhibition. Overall, the present results confirm that I inhibits mTORC1 activity. This is dependent on the presence of TSC2, and inhibition of mTORC1 contributes to optimal 1-induced growth inhibition. Inhibition of RNA translation may be an important component of the antitumor effects of phenethyl isothiocyanate.