A novel derivative of betulinic acid, SYK023, suppresses lung cancer growth and malignancy
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Tsung-I Hsu1,2, Ying-Jung Chen2, Chia-Yang Hung3, Yi-Chang Wang3, Sin-Jin Lin2, Wu-Chou Su4, Ming-Derg Lai1,3,5, Sang-Yong Kim6, Qiang Wang6, Keduo Qian6, Masuo Goto6, Yu Zhao6, Yoshiki Kashiwada7, Kuo-Hsiung Lee6,8, Wen-Chang Chang1,2,3,9,10 and Jan-Jong Hung1,2,3,9,10
1 Center for Infection Disease and Signal Research, College of Medicine, National Cheng Kung University, Tainan, Taiwan
2 Institute of Bioinformatics and Biosignal Transduction, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan, Taiwan
3 Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan
4 Department of Internal Medicine, College of Medicine and Hospital, National Cheng Kung University, Tainan, Taiwan
5 Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
6 Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, USA
7 Laboratory of Pharmacognosy, Graduate School of Pharmaceutical Sciences, The University of Tokushima, Tokushima, Japan
8 Chinese Medicine Research and Development Center, China Medical University and Hospital, Taichung, Taiwan
9 Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
10 Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan
Jan-Jong Hung, email:
Wen-Chang Chang, email:
Kuo-Hsiung Lee, email:
Keywords: SYK023, ER stress, metastasis, synaptopodin
Received: November 03, 2014 Accepted: March 02, 2015 Published: March 30, 2015
Herein, we evaluated the anti-cancer effect and molecular mechanisms of a novel betulinic acid (BA) derivative, SYK023, by using two mouse models of lung cancer driven by KrasG12D or EGFRL858R. We found that SYK023 inhibits lung tumor proliferation, without side effects in vivo or cytotoxicity in primary lung cells in vitro. SYK023 triggered endoplasmic reticulum (ER) stress. Blockage of ER stress in SYK023-treated cells inhibited SYK023-induced apoptosis. In addition, we found that the expression of cell cycle-related genes, including cyclin A2, B1, D3, CDC25a, and CDC25b decreased but, while those of p15INK4b, p16INK4a, and p21CIP1 increased following SYK023 treatment. Finally, low doses of SYK023 significantly decreased lung cancer metastasis in vitro and in vivo. Expression of several genes related to cell migration, including synaptopodin, were downregulated by SYK023, thereby impairing F-actin polymerization and metastasis. Therefore, SYK023 may be a potentially therapeutic treatment for metastatic lung cancer.
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