Mechanistic elucidation of the antitumor properties of withaferin a in breast cancer.
Mechanistic elucidation of the antitumor properties of withaferin a in breast cancer.
复制标题
DOI：
10.1158/0008-5472.can-13-2081
复制
发表时间：
2014-05-01
期刊：
影响因子：
11.2
通讯作者：
Saxena NK
中科院分区：
文献类型：
--
作者：
Nagalingam A;Kuppusamy P;Singh SV;Sharma D;Saxena NK
Withaferin A（WFA）是一种甾体内酯，具有多水平的抗肿瘤作用，其机制尚不清楚。使用磷酸激酶筛选阵列，我们发现WFA激活乳腺癌细胞中S6激酶RSK的磷酸化。根据这一观察结果，我们确定了ERK-RSK和Elk 1-CHOP激酶通路在上调死亡受体DR 5转录中的激活。通过这一途径，WFA作为一种有效的DR 5激活剂，能够增强塞来昔布、依托泊苷和TRAIL的生物学效应。因此，WFA处理以与ERK/RSK轴激活、DR 5上调和Elk 1和CHOP核蓄积升高相关的方式抑制异种移植物和MMTV-neu小鼠模型中的乳腺肿瘤形成。总之，我们的研究结果提供了WFA如何抑制乳腺肿瘤生长的机制见解。
Withaferin A (WFA) is a steroidal lactone with antitumor effects manifested at multiple levels which are mechanistically obscure. Using a phospho-kinase screening array, we discovered that WFA activated phosphorylation of the S6 kinase RSK in breast cancer cells. Pursuing this observation, we defined activation of ERK-RSK and Elk1-CHOP kinase pathways in upregulating transcription of the death receptor DR5. Through this route, WFA acted as an effective DR5 activator capable of potentiating the biological effects of celecoxib, etoposide and TRAIL. Accordingly, WFA treatment inhibited breast tumor formation in xenograft and MMTV-neu mouse models in a manner associated with activation of the ERK/RSK axis, DR5 upregulation and elevated nuclear accumulation of Elk1 and CHOP. Together, our results offer mechanistic insight into how WFA inhibits breast tumor growth.