Work

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

Year: 2016

Type: article

Abstract: // Min Shi 1, * , Xiao-Jie Lu 2, 1, * , Juan Zhang 3 , Hua Diao 4 , Guangming Li 5 , Ling Xu 1 , Ting Wang 1 , Jue Wei 1 , Wenying Meng 1 , Jia-Li Ma 1 , Heguo Yu 4 , Yu-Gang Wang 1 1 Department of Gastroenterology, Shanghai Tongren Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China 2 Department of Radiology, Zhong-da Hospital, Medical School, Southeast University, Nanjing, China 3 Department of Rehabilitation, The Affiliated Huai’an Hospital of Xuzhou Medical College and The Second People’s Hospital of Huai’an, Huai’an, China 4 NPFPC Key Laboratory of Contraceptives and Devices, Shanghai Institute of Planned Parenthood Research (SIPPR), Institutes of Reproduction and Development, Fudan University, Shanghai, China 5 Department 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: [email protected] Heguo Yu, e-mail: [email protected] 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.

Source: Oncotarget

DOI: 10.18632/oncotarget.8033