Song Yarong, Zhang Peng, Sun Yadong, Li Xuechao, Chen Lifeng, Xiao Yajun, Xing Yifei
Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
Oncotarget. 2017 Jul 4;8(40):67942-67954. doi: 10.18632/oncotarget.18980. eCollection 2017 Sep 15.
Autophagy is an evolutionarily conserved catabolic process in eukaryotic cells, which allows cells to overcome a wide array of of stresses and has recently been shown to result in drug resistance. This study examined the effect of autophagy on oleanolic acid (OA)-induced cytotoxicity against bladder cancer cells. Our study demonstrated that OA inhibited cell viability, proliferation, and induced apoptosis in bladder cancer lines T24 and EJ. Furthermore, OA induced autophagy in both cell lines by activating AMP-activated protein kinase (AMPK), inhibiting mechanistic target of rapamycin (mTOR) and promoting unc-51 like autophagy activating kinase 1 (ULK1). Moreover, inhibiting autophagy by siRNA to autophagy related 7 (ATG7) or with autophagy inhibitor bafilomycin A1 and 3-methyladenine (3-MA) or AMPK inhibitor dorsomorphin (compound C) promoted OA-induced deaths of bladder cancer cells. In contrast, either autophagy activator rapamycin or AMPK activator acadesine (AICAR) compromised OA-induced anti-cancer effect. Our findings suggested that OA induced protective autophagy through AMPK-mTOR-ULK1 signaling pathway in bladder cancer cells and OA in combination with autophagy inhibitor might be a novel alternative for the treatment of bladder cancer.
自噬是真核细胞中一种进化上保守的分解代谢过程，它使细胞能够克服多种应激，并且最近已被证明会导致耐药性。本研究考察了自噬对齐墩果酸（OA）诱导的膀胱癌细胞毒性的影响。我们的研究表明，OA抑制膀胱癌细胞系T24和EJ的细胞活力、增殖并诱导凋亡。此外，OA通过激活AMP活化蛋白激酶（AMPK）、抑制雷帕霉素靶蛋白（mTOR）并促进自噬相关蛋白51样自噬激活激酶1（ULK1），在这两种细胞系中诱导自噬。而且，通过针对自噬相关蛋白7（ATG7）的小干扰RNA（siRNA），或使用自噬抑制剂巴弗洛霉素A1和3-甲基腺嘌呤（3-MA），或AMPK抑制剂 dorsomorphin（化合物C）抑制自噬，可促进OA诱导的膀胱癌细胞死亡。相反，自噬激活剂雷帕霉素或AMPK激活剂阿卡地新（AICAR）会削弱OA诱导的抗癌作用。我们的研究结果表明，OA通过AMPK-mTOR-ULK1信号通路在膀胱癌细胞中诱导保护性自噬，并且OA与自噬抑制剂联合使用可能是治疗膀胱癌的一种新选择。
