Dihydroartemisinin selectively inhibits PDGFRα-positive ovarian cancer growth and metastasis through inducing degradation of PDGFRα protein.
Dihydroartemisinin selectively inhibits PDGFRα-positive ovarian cancer growth and metastasis through inducing degradation of PDGFRα protein.
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双氢青蒿素通过诱导 PDGFR α 蛋白降解选择性抑制 PDGFR α 阳性卵巢癌的生长和转移
DOI：
10.1038/celldisc.2017.42
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发表时间：
2017
期刊：
影响因子：
33.5
通讯作者：
Wang H
中科院分区：
文献类型：
--
作者：
Li X;Ba Q;Liu Y;Yue Q;Chen P;Li J;Zhang H;Ying H;Ding Q;Song H;Liu H;Zhang R;Wang H
为了将传统药物发展为现代药物疗法，了解其作用的分子机制可能非常有帮助。近年来，青蒿素及其衍生物作为临床上常用的抗疟疾药物，对卵巢癌有显著的疗效，但其直接的分子靶点及相关的联合治疗尚不清楚。在此，我们报道了双氢青蒿素，青蒿素的最有效的衍生物之一，直接靶向血小板衍生生长因子受体-α（PDGFRα），以抑制卵巢癌细胞的生长和转移。双氢青蒿素直接与PDGFRα的细胞间结构域结合，通过加速其泛素介导的降解降低其蛋白质稳定性，从而进一步灭活下游磷酸肌醇3-激酶和丝裂原活化蛋白激酶途径，随后抑制上皮-间质转化，在体外和体内抑制PDGFRα阳性卵巢癌的细胞生长和转移。联合治疗显示，双氢青蒿素使卵巢癌细胞对PDGFR抑制剂敏感。我们的临床研究也发现PDGFRα在人卵巢癌中过表达，且与卵巢癌的高分级和转移呈正相关。考虑到青蒿素化合物目前是临床使用的药物，具有良好的安全性特征，本研究的结果将加强其与临床使用的PDGFRα抑制剂的联合使用，从而在PDGFRα阳性癌症患者中获得最大的治疗疗效和最小的不良反应。这些发现也为未来基于青蒿素的新型靶向治疗的发展提供了重要启示。
To develop traditional medicines as modern pharmacotherapies, understanding their molecular mechanisms of action can be very helpful. We have recently reported that Artemisinin and its derivatives, which are clinically used anti-malarial drugs, have significant effects against ovarian cancer, but the direct molecular targets and related combination therapy have been unclear. Herein, we report that dihydroartemisinin, one of the most active derivatives of Artemisinin, directly targets platelet-derived growth factor receptor-alpha (PDGFRα) to inhibit ovarian cancer cell growth and metastasis. Dihydroartemisinin directly binds to the intercellular domain of PDGFRα, reducing its protein stability by accelerating its ubiquitin-mediated degradation, which further inactivates downstream phosphoinositide 3-Kinase and mitogen-activated protein kinase pathways and subsequently represses epithelial–mesenchymal transition, inhibiting cell growth and metastasis of PDGFRα-positive ovarian cancer in vitro and in vivo. A combinational treatment reveals that dihydroartemisinin sensitizes ovarian cancer cells to PDGFR inhibitors. Our clinical study also finds that PDGFRα is overexpressed and positively correlated with high grade and metastasis in human ovarian cancer. Considering that Artemisinin compounds are currently clinically used drugs with favorable safety profiles, the results from this study will potentiate their use in combination with clinically used PDGFRα inhibitors, leading to maximal therapeutic efficacy with minimal adverse effects in PDGFRα-positive cancer patients. These findings also shed high light on future development of novel Artemisinin-based targeted therapy.
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影响因子：
64.8
作者：
通讯作者：
--
浆液卵巢癌中试剂盒和PDGFRA的遗传改变和蛋白质表达。
影响因子：
8.8
作者：
Lassus, H;Sihto, H;Leminen, A;Nordling, S;Joensuu, H;Nupponen, NN;Butzow, R
通讯作者：
Butzow, R
DOI：
10.1038/nrc2644
发表时间：
2009-06
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
通讯作者：
--
影响因子：
4.7
作者：
Matsuo K;Nishimura M;Komurov K;Shahzad MM;Ali-Fehmi R;Roh JW;Lu C;Cody DD;Ram PT;Loizos N;Coleman RL;Sood AK
通讯作者：
Sood AK
影响因子：
15.9
作者：
Jechlinger, Martin;Sommer, Andreas;Gruenert, Stefan
通讯作者：
Gruenert, Stefan