Notch-1 inhibition by Withaferin-A: a therapeutic target against colon carcinogenesis.
Notch-1 inhibition by Withaferin-A: a therapeutic target against colon carcinogenesis.
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DOI：
10.1158/1535-7163.mct-09-0771
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发表时间：
2010-01
影响因子：
5.7
通讯作者：
Damodaran C
中科院分区：
文献类型：
--
作者：
Koduru S;Kumar R;Srinivasan S;Evers MB;Damodaran C
Notch signaling plays a crucial role in the development of colon cancer; targeting the Notch pathway may sensitize colon cancers to various adjuvant agents. The focus of our current study is to identify natural compounds that target Notch signaling and that might be beneficial for the prevention and treatment of colon cancer. Withaferin-A (WA) is a bioactive compound derived from Withania somnifera, which inhibits Notch-1 signaling and downregulates pro-survival pathways, such as Akt/NF-κB/Bcl-2, in three colon cancer cell lines (HCT-116, SW-480 and SW-620). In addition, WA downregulated expression of mTOR signaling components, pS6K and p4E-BP1 and activated JNK-mediated apoptosis in colon cancer cells. We also established the molecular link between Notch/Akt/mTOR signaling by complementary approaches (i.e., overexpression of Notch-1 or inhibition of Notch-1 by siRNA). Our results suggest that WA inhibits Notch-mediated pro-survival signaling, which facilitates JNK mediated apoptosis in colon cancer cell lines. These results underscore the anti-cancer activity of WA, which exhibits potential for further development for targeted chemotherapy and/or chemoprevention strategies in the context of colon cancer.
