Oncotarget

Research Papers:

Oridonin, a novel lysine acetyltransferases inhibitor, inhibits proliferation and induces apoptosis in gastric cancer cells through p53- and caspase-3-mediated mechanisms

Min Shi, Xiao-Jie Lu, Juan Zhang, Hua Diao, Guangming Li, Ling Xu, Ting Wang, Jue Wei, Wenying Meng, Jia-Li Ma, Heguo Yu and Yu-Gang Wang _

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Oncotarget. 2016; 7:22623-22631. https://doi.org/10.18632/oncotarget.8033

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Abstract

Min Shi1,*, Xiao-Jie Lu2,1,*, Juan Zhang3, Hua Diao4, Guangming Li5, Ling Xu1, Ting Wang1, Jue Wei1, Wenying Meng1, Jia-Li Ma1, Heguo Yu4, Yu-Gang Wang1

1Department of Gastroenterology, Shanghai Tongren Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China

2Department of Radiology, Zhong-da Hospital, Medical School, Southeast University, Nanjing, China

3Department of Rehabilitation, The Affiliated Huai’an Hospital of Xuzhou Medical College and The Second People’s Hospital of Huai’an, Huai’an, China

4NPFPC Key Laboratory of Contraceptives and Devices, Shanghai Institute of Planned Parenthood Research (SIPPR), Institutes of Reproduction and Development, Fudan University, Shanghai, China

5Department of Gastroenterology, Xinhua Hospital, Shanghai Second Medical University, Shanghai, China

*These authors have contributed equally to this work

Correspondence to:

Yu-Gang Wang, e-mail: wangyugang2013@yeah.net

Heguo Yu, e-mail: yuheguo@163.com

Keywords: oridonin, lysine acetyltransferase inhibitor, gastric cancer, antiproliferation, apoptosis

Received: January 30, 2016     Accepted: February 23, 2016     Published: March 10, 2016

ABSTRACT

Lysine acetylation has been reported to involve in the pathogenesis of multiple diseases including cancer. In our screening study to identify natural compounds with lysine acetyltransferase inhibitor (KATi) activity, oridonin was found to possess acetyltransferase-inhibitory effects on multiple acetyltransferases including P300, GCN5, Tip60, and pCAF. In gastric cancer cells, oridonin treatment inhibited cell proliferation in a concentration-dependent manner and down-regulated the expression of p53 downstream genes, whereas p53 inhibition by PFT-α reversed the antiproliferative effects of oridonin. Moreover, oridonin treatment induced cell apoptosis, increased the levels of activated caspase-3 and caspase-9, and decreased the mitochondrial membrane potential in gastric cancer cells in a concentration-dependent manner. Caspase-3 inhibition by Ac-DEVD-CHO reversed the proapoptosis effect of oridonin. In conclusion, our study identified oridonin as a novel KATi and demonstrated its tumor suppressive effects in gastric cancer cells at least partially through p53-and caspase-3-mediated mechanisms.


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