Ancient drug curcumin impedes 26S proteasome activity by direct inhibition of dual-specificity tyrosine-regulated kinase 2.
Ancient drug curcumin impedes 26S proteasome activity by direct inhibition of dual-specificity tyrosine-regulated kinase 2.
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古老药物姜黄素通过直接抑制双特异性酪氨酸调节激酶2来阻碍26S蛋白酶体活性
DOI：
10.1073/pnas.1806797115
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发表时间：
2018-08-07
影响因子：
11.1
通讯作者：
Guo X
中科院分区：
文献类型：
--
作者：
Banerjee S;Ji C;Mayfield JE;Goel A;Xiao J;Dixon JE;Guo X
姜黄素是一种源自姜黄的古老药物，尽管作用机制存在争议，但已被发现具有有效的抗癌特性。使用生物化学模型，小鼠癌症模型和细胞模型，我们表明，姜黄素是一种高度有效的和选择性的双特异性酪氨酸调节激酶2（DYRK 2），26 S蛋白酶体的正调节剂抑制剂。姜黄素通过在各种癌细胞和小鼠癌症模型中抑制DYRK 2干扰26 S蛋白酶体活性，导致小鼠中细胞增殖受损和癌症负荷降低。姜黄素的这种新的作用机制为蛋白酶体成瘾性癌症（如三阴性乳腺癌和多发性骨髓瘤）的潜在预防或治疗策略开辟了新的途径。姜黄素是姜黄中的活性成分，自古以来就有药用价值。然而，尽管进行了广泛的研究，但姜黄素调节的治疗靶点和信号级联反应一直是个谜。在这里，我们确定双特异性酪氨酸调节激酶2（DYRK 2），26 S蛋白酶体的正调节剂，作为姜黄素的直接靶点。姜黄素占据共晶体结构中DYRK 2的ATP结合口袋，并且它在体外测试的139种其他激酶中有效且特异性地抑制DYRK 2。因此，姜黄素减少细胞中DYRK 2介导的26 S蛋白酶体磷酸化，导致蛋白酶体活性降低和细胞增殖受损。有趣的是，姜黄素与治疗性蛋白酶体抑制剂卡非佐米协同作用，诱导各种蛋白酶体成瘾癌细胞的凋亡，而这种药物组合对非癌细胞表现出适度至无细胞毒性。在乳腺癌异种移植模型中，姜黄素治疗显著降低了免疫功能低下小鼠的肿瘤负荷，显示出与CRISPR/Cas9介导的DYRK 2耗竭相似的抗肿瘤作用。这些结果揭示了姜黄素在DYRK 2蛋白酶体抑制中意想不到的作用，并提供了概念验证，即蛋白酶体调节剂的药理学操作可能为抗癌治疗提供新的机会。
Significance Curcumin is an ancient drug derived from turmeric and has been found to exhibit potent anticancer properties albeit through controversial mechanisms of action. Using a biochemical model, mouse cancer model, and cellular models, we show that curcumin is a highly potent and selective inhibitor of dual-specificity tyrosine-regulated kinase 2 (DYRK2), a positive regulator of the 26S proteasome. Curcumin perturbs 26S proteasome activity via DYRK2 inhibition in various cancer cells and in the mouse cancer model leading to impairment of cell proliferation and reduction of cancer burden in mice. This novel mechanism of action of curcumin opens up new avenues for potential preventative or therapeutic strategies in proteasome-addicted cancers like triple-negative breast cancer and multiple myeloma. Curcumin, the active ingredient in Curcuma longa, has been in medicinal use since ancient times. However, the therapeutic targets and signaling cascades modulated by curcumin have been enigmatic despite extensive research. Here we identify dual-specificity tyrosine-regulated kinase 2 (DYRK2), a positive regulator of the 26S proteasome, as a direct target of curcumin. Curcumin occupies the ATP-binding pocket of DYRK2 in the cocrystal structure, and it potently and specifically inhibits DYRK2 over 139 other kinases tested in vitro. As a result, curcumin diminishes DYRK2-mediated 26S proteasome phosphorylation in cells, leading to reduced proteasome activity and impaired cell proliferation. Interestingly, curcumin synergizes with the therapeutic proteasome inhibitor carfilzomib to induce apoptosis in a variety of proteasome-addicted cancer cells, while this drug combination exhibits modest to no cytotoxicity to noncancerous cells. In a breast cancer xenograft model, curcumin treatment significantly reduces tumor burden in immunocompromised mice, showing a similar antitumor effect as CRISPR/Cas9-mediated DYRK2 depletion. These results reveal an unexpected role of curcumin in DYRK2-proteasome inhibition and provide a proof-of-concept that pharmacological manipulation of proteasome regulators may offer new opportunities for anticancer treatment.
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影响因子：
64.5
作者：
López-Otín C;Blasco MA;Partridge L;Serrano M;Kroemer G
通讯作者：
Kroemer G
影响因子：
7.3
作者：
Nelson KM;Dahlin JL;Bisson J;Graham J;Pauli GF;Walters MA
通讯作者：
Walters MA
位点特异性蛋白酶体磷酸化控制细胞增殖和肿瘤发生。
影响因子：
21.3
作者：
Guo X;Wang X;Wang Z;Banerjee S;Yang J;Huang L;Dixon JE
通讯作者：
Dixon JE
影响因子：
4.7
作者：
Neuss, Heiko;Huang, Xiaohua;Dubiel, Wolfgang
通讯作者：
Dubiel, Wolfgang
影响因子：
32.4
作者：
Chang JT;Ciocca ML;Kinjyo I;Palanivel VR;McClurkin CE;Dejong CS;Mooney EC;Kim JS;Steinel NC;Oliaro J;Yin CC;Florea BI;Overkleeft HS;Berg LJ;Russell SM;Koretzky GA;Jordan MS;Reiner SL
通讯作者：
Reiner SL