期刊
ONCOTARGET
卷 6, 期 15, 页码 13671-13687出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.3701
关键词
SYK023; ER stress; metastasis; synaptopodin
资金
- Tissue Bank, Research Center of Clinical Medicine, National Cheng Kung University Hospital
- Program for Promoting Academic Excellence and Developing World Class Research Centers of National Cheng Kung University
- Ministry of Science and Technology, Taiwan [100-2320-B-038-032-MY3, 101-2321-B-006-004-MY3, 103-2120-M-006-006]
- Food and Drug Administration, Ministry of Health and Welfare, Executive Yuan, Taiwan [MOHW103-TD-B-111-06, MOHW103-TDU-B-211-113002]
- NIH from the National Cancer Institute [CA177584]
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 Kras(G12D) or EGFR(L858R). 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 p15(INK4b), p16(INK4a), and p21(CIP1) 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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