Oridonin inhibits aberrant AKT activation in breast cancer
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Bowen Sun1,2, Geng Wang2,3, Huidong Liu2,3, Pian Liu4, Waleed O. Twal5, Hiuwing Cheung2, Steven L. Carroll2, Stephen P. Ethier2, Emily E. Mevers6, Jon Clardy6, Thomas Roberts6,7, Changbin Chen8, Qian Li8, Lanfeng Wang8, Meixiang Yang1, Jean J. Zhao6,7 and Qi Wang2
1The first Affiliate Hospital, Biomedical Translational Research Institute, Guangdong Province Key Laboratory of Molecular Immunology and Antibody Engineering, Jinan University, Guangzhou 510632, China
2Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC 29425, USA
3Department of Anatomy, Harbin Medical University, Harbin 150081, China
4Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China
5Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29425, USA
6Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA
7Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA
8Institute Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200031, China
Jean J. Zhao, email: [email protected]
Qi Wang, email: [email protected]
Keywords: TCM plant extracts; oridonin; PI3K/AKT signaling; mammary tumor prevention; tumorigenesis
Received: October 17, 2017 Accepted: January 13, 2018 Epub: February 01, 2018 Published: May 08, 2018
Aberrant activation of phosphatidylinosito-4,5-bisphosphate 3-kinase/protein kinase B (PI3K/AKT) signaling in cancer has led to pursuit of inhibitors for targeting this pathway. However, inhibitors of PI3K and AKT have failed to yield efficacious results without adverse effects. Here, we screened a library containing 441 authenticated traditional chinese medicine (TCM) plant extracts by examining their effect on cell viability of a human mammary epithelial cell line HMEC-PIK3CAH1047R, which expresses mutant PIK3CAH1047R and has constitutively active AKT signaling. We found that Oridonin, an extract from Rabdosia rubescens, reduced cell viability to the greatest extent. Oridonin binds to AKT1 and potentially functions as an ATP-competitive AKT inhibitor. Importantly, Oridonin selectively impaired tumor growth of human breast cancer cells with hyperactivation of PI3K/AKT signaling. Moreover, Oridonin prevented the initiation of mouse mammary tumors driven by PIK3CAH1047R. Our results suggest that Oridonin may serve as a potent and durable therapeutic agent for the treatment of breast cancers with hyperactivation of PI3K/AKT signaling.
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