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Tubeimoside-1, a triterpenoid saponin, induces cytoprotective autophagy in human breast cancer cells in vitro via Akt-mediated pathway

Authors: Shi-long Jiang1, Yi-di Guan1, Xi-sha Chen1, Peng Ge1, Xin-luan Wang2, Yuan-zhi Lao3, Song-shu Xiao4, Yi Zhang5, Jin-ming Yang6, Xiao-jun Xu7, Dong-sheng Cao1,8, Yan Cheng1,8
1 Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410008, China
2 Translational Medicine R&D Center, Institute of Biomedical and Health Engineering, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518057, China
3 School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
4 Department of Gynecology and Obstetrics, The Third Xiangya Hospital, Central South University, Changsha 410008, China
5 Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou 215000, China
6 Department of Pharmacology, The Penn State Hershey Cancer Institute, The Pennsylvania State University College of Medicine and Milton S Hershey Medical Center, Hershey, PA, USA
7 State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
8 Department of Dermatology, Xiangya Hospital, Central South University, Changsha 410008, China
Correspondence to: Dong-sheng Cao: oriental-cds@163.com, Yan Cheng: chengyan0677@163.com,
DOI: 10.1038/s41401-018-0165-9
Received: 15 May 2018
Accepted: 28 August 2018
Advance online: 12 October 2018

Abstract

Autophagy, a form of cellular self-digestion by lysosome, is associated with various disease processes including cancers, and modulating autophagy has shown promise in the treatment of various malignancies. A number of natural products display strong antitumor activity, yet their mechanisms of action remain unclear. To gain a better understanding of how traditional Chinese medicine agents exert antitumor effects, we screened 480 natural compounds for their effects on autophagy using a high content screening assay detecting GFP-LC3 puncta in HeLa cells. Tubeimoside-1 (TBMS1), a triterpenoid saponin extracted from Bolbostemma paniculatum (Maxim) Franquet (Cucurbitaceae), was identified as a potent activator of autophagy. The activation of autophagy by TBMS1 was evidenced by increased LC3-II amount and GFP-LC3 dots, observation of autophagosomes under electron microscopy, and enhanced autophagic flux. To explore the mechanisms underlying TBMS1-activated autophagy, we performed cheminformatic analyses and surface plasmon resonance (SPR) binding assay that showed a higher likelihood of the binding between Akt protein and TBMS1. In three human breast cancer cell lines, we demonstrated that Akt–mTOR–eEF-2K pathway was involved in TBMS1-induced activation of autophagy, while Akt-mediated downregulations of Mcl-1, Bcl-xl, and Bcl-2 led to the activation of apoptosis of the breast cancer cells. Inhibition of autophagy enhanced the cytotoxic effect of TBMS1 via promoting apoptosis. Our results demonstrate the role and mechanism of TBMS1 in activating autophagy, suggesting that inhibition of cytoprotective autophagy may act as a therapeutic strategy to reinforce the activity of TBMS1 against cancers.
Keywords: tubeimoside-1; autophagy; apoptosis; Akt; breast cancer cells

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