Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, USA.
J Biol Chem. 2010 Nov 12;285(46):35528-36. doi: 10.1074/jbc.M110.152686. Epub 2010 Sep 10.
It is conceivable that stimulating proteasome activity for rapid removal of misfolded and oxidized proteins is a promising strategy to prevent and alleviate aging-related diseases. Sulforaphane (SFN), an effective cancer preventive agent derived from cruciferous vegetables, has been shown to enhance proteasome activities in mammalian cells and to reduce the level of oxidized proteins and amyloid β-induced cytotoxicity. Here, we report that SFN activates heat shock transcription factor 1-mediated heat shock response. Specifically, SFN-induced expression of heat shock protein 27 (Hsp27) underlies SFN-stimulated proteasome activity. SFN-induced proteasome activity was significantly enhanced in Hsp27-overexpressing cells but absent in Hsp27-silenced cells. The role of Hsp27 in regulating proteasome activity was further confirmed in isogenic REG cells, in which SFN-induced proteasome activation was only observed in cells stably overexpressing Hsp27, but not in the Hsp27-free parental cells. Finally, we demonstrated that phosphorylation of Hsp27 is irrelevant to SFN-induced proteasome activation. This study provides a novel mechanism underlying SFN-induced proteasome activity. This is the first report to show that heat shock response by SFN, in addition to the antioxidant response mediated by the Keap1-Nrf2 pathway, may contribute to cytoprotection.
可以想象，刺激蛋白酶体活性以快速清除错误折叠和氧化的蛋白质是预防和缓解与衰老相关疾病的一种有前途的策略。 西兰花等十字花科蔬菜中提取的有效抗癌物质——萝卜硫素（SFN）已被证明可以增强哺乳动物细胞中的蛋白酶体活性，并降低氧化蛋白和淀粉样β诱导的细胞毒性水平。在这里，我们报告 SFN 可激活热休克转录因子 1 介导的热休克反应。具体来说，SFN 诱导热休克蛋白 27（Hsp27）的表达是 SFN 刺激蛋白酶体活性的基础。SFN 诱导的蛋白酶体活性在 Hsp27 过表达细胞中显著增强，但在 Hsp27 沉默细胞中不存在。在同基因 REG 细胞中进一步证实了 Hsp27 在调节蛋白酶体活性中的作用，其中仅在稳定过表达 Hsp27 的细胞中观察到 SFN 诱导的蛋白酶体激活，而在没有 Hsp27 的亲本细胞中则没有。最后，我们证明 Hsp27 的磷酸化与 SFN 诱导的蛋白酶体激活无关。这项研究提供了 SFN 诱导蛋白酶体活性的新机制。这是首次报道 SFN 通过热休克反应（除了 Keap1-Nrf2 通路介导的抗氧化反应）可能有助于细胞保护。
