Hsu Tsung-I, Chen Ying-Jung, Hung Chia-Yang, Wang Yi-Chang, Lin Sin-Jin, Su Wu-Chou, Lai Ming-Derg, Kim Sang-Yong, Wang Qiang, Qian Keduo, Goto Masuo, Zhao Yu, Kashiwada Yoshiki, Lee Kuo-Hsiung, Chang Wen-Chang, Hung Jan-Jong
Center for Infection Disease and Signal Research, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Institute of Bioinformatics and Biosignal Transduction, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan, Taiwan.
Oncotarget. 2015 May 30;6(15):13671-87. doi: 10.18632/oncotarget.3701.
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.
在此，我们通过使用由KrasG12D或EGFRL858R驱动的两种肺癌小鼠模型，评估了一种新型桦木酸（BA）衍生物SYK023的抗癌作用及其分子机制。我们发现SYK023可抑制肺肿瘤增殖，在体内无副作用，在体外对原代肺细胞无细胞毒性。SYK023引发内质网（ER）应激。在经SYK023处理的细胞中阻断ER应激可抑制SYK023诱导的细胞凋亡。此外，我们发现，经SYK023处理后，细胞周期相关基因（包括细胞周期蛋白A2、B1、D3、细胞分裂周期蛋白25a和细胞分裂周期蛋白25b）的表达降低，而p15INK4b、p16INK4a和p21CIP1的表达增加。最后，低剂量的SYK023在体外和体内均显著降低肺癌转移。SYK023下调了包括突触足蛋白在内的几种与细胞迁移相关基因的表达，从而损害F-肌动蛋白聚合和转移。因此，SYK023可能是转移性肺癌的一种潜在治疗方法。
