Oridonin inhibits aberrant AKT activation in breast cancer

Bowen Sun; Geng Wang; Huidong Liu; Pian Liu; Waleed O Twal; Hiuwing Cheung; Steven L Carroll; Stephen P Ethier; Emily E Mevers; Jon Clardy; Thomas Roberts; Changbin Chen; Qian Li; Lanfeng Wang; Meixiang Yang; Jean J Zhao; Qi Wang

doi:10.18632/oncotarget.24378

Oridonin inhibits aberrant AKT activation in breast cancer

Oncotarget. 2018 Feb 1;9(35):23878-23889. doi: 10.18632/oncotarget.24378. eCollection 2018 May 8.

Authors

Bowen Sun^{1

2}, Geng Wang^{2

3}, Huidong Liu^{2

3}, Pian Liu⁴, Waleed O Twal⁵, Hiuwing Cheung², Steven L Carroll², Stephen P Ethier², Emily E Mevers⁶, Jon Clardy⁶, Thomas Roberts^{6

7}, Changbin Chen⁸, Qian Li⁸, Lanfeng Wang⁸, Meixiang Yang¹, Jean J Zhao^{6

7}, Qi Wang²

Affiliations

¹ The first Affiliate Hospital, Biomedical Translational Research Institute, Guangdong Province Key Laboratory of Molecular Immunology and Antibody Engineering, Jinan University, Guangzhou 510632, China.
² Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC 29425, USA.
³ Department of Anatomy, Harbin Medical University, Harbin 150081, China.
⁴ Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China.
⁵ Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29425, USA.
⁶ Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
⁷ Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
⁸ Institute Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200031, China.

Abstract

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-PIK3CA^H1047R, which expresses mutant PIK3CA^H1047R 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 PIK3CA^H1047R. 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.

Keywords: PI3K/AKT signaling; TCM plant extracts; mammary tumor prevention; oridonin; tumorigenesis.

Abstract

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