Bafilomycin A1 induces caspase-independent cell death in hepatocellular carcinoma cells via targeting of autophagy and MAPK pathways.
Bafilomycin A1 induces caspase-independent cell death in hepatocellular carcinoma cells via targeting of autophagy and MAPK pathways.
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Bafilomycin A1 通过靶向自噬和 MAPK 途径诱导肝细胞癌细胞中不依赖 caspase 的细胞死亡
DOI：
10.1038/srep37052
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发表时间：
2016-11-15
影响因子：
4.6
通讯作者：
Gong P
中科院分区：
文献类型：
--
作者：
Yan Y;Jiang K;Liu P;Zhang X;Dong X;Gao J;Liu Q;Barr MP;Zhang Q;Hou X;Meng S;Gong P
肝细胞癌（HCC）是化疗难治性的，需要新的有效药物。高浓度的溶酶体抑制剂巴弗洛霉素A1（BafA 1）在多种癌症中显示出细胞毒性。在这里，我们表明，BafA 1在纳摩尔浓度抑制肝癌细胞生长在二维（2D）和三维文化。BafA 1以双特异性酪氨酸磷酸化调节激酶1B（DYRK 1B）依赖的方式诱导肝癌细胞周期停滞在G1期并触发细胞周期蛋白D1的更新。值得注意的是，BafA 1通过损害自噬通量诱导HCC细胞中的半胱天冬酶非依赖性细胞死亡，如升高的LC 3转化和p62/SQSTM 1水平所证明的。此外，LC 3的基因切除显著减弱了BafA 1诱导的HCC细胞的细胞毒性。我们进一步证明，药理学下调或基因耗竭p38 MAPK减少BafA 1诱导的细胞死亡，通过废除BafA 1诱导的Puma上调。值得注意的是，Puma的敲低削弱了BafA 1诱导的HCC细胞死亡，而Puma的过表达增强了BafA 1介导的HCC细胞死亡，这表明Puma在BafA 1介导的细胞毒性中的作用。有趣的是，SP 600125对JNK的药理学抑制增强了BafA 1介导的细胞毒性，无论是在体外还是在源自HCC细胞的异种移植物中。综上所述，我们的数据表明BafA 1可能作为HCC的有效疗法提供潜力。
Hepatocellular carcinoma (HCC) is refractory to chemotherapies, necessitating novel effective agents. The lysosome inhibitor Bafilomycin A1 (BafA1) at high concentrations displays cytotoxicity in a variety of cancers. Here we show that BafA1 at nanomolar concentrations suppresses HCC cell growth in both 2 dimensional (2D) and 3D cultures. BafA1 induced cell cycle arrest in the G1 phase and triggered Cyclin D1 turnover in HCC cells in a dual-specificity tyrosine phosphorylation-regulated kinase 1B (DYRK1B) dependent manner. Notably, BafA1 induced caspase-independent cell death in HCC cells by impairing autophagy flux as demonstrated by elevated LC3 conversion and p62/SQSTM1 levels. Moreover, genetic ablation of LC3 significantly attenuated BafA1-induced cytotoxicity of HCC cells. We further demonstrate that pharmacological down-regulation or genetic depletion of p38 MAPK decreased BafA1-induced cell death via abolishment of BafA1-induced upregulation of Puma. Notably, knockdown of Puma impaired BafA1-induced HCC cell death, and overexpression of Puma enhanced BafA1-mediated HCC cell death, suggesting a role for Puma in BafA1-mediated cytotoxicity. Interestingly, pharmacological inhibition of JNK with SP600125 enhanced BafA1-mediated cytotoxicity both in vitro and in xenografts derived from HCC cells. Taken together, our data suggest that BafA1 may offer potential as an effective therapy for HCC.
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DOI：
10.1016/j.bbrc.2009.03.051
发表时间：
2009-05-01
影响因子：
3.1
作者：
Wu, Ya Chun;Wu, William Ka Kei;Cho, Chi Hin
通讯作者：
Cho, Chi Hin
人肝细胞癌中液泡H-ATP酶的表达及其功能作用
影响因子：
4.7
作者：
Xu, Jingyu;Xie, Rui;Tuo, Biguang
通讯作者：
Tuo, Biguang
影响因子：
15.9
作者：
Bellodi, Cristian;Lidonnici, Maria Rosa;Calabretta, Bruno
通讯作者：
Calabretta, Bruno
影响因子：
3.5
作者：
Kinoshita, K;Waritani, T;Ohkuma, S
通讯作者：
Ohkuma, S
影响因子：
2.7
作者：
Nakashima, S;Hiraku, Y;Kawanishi, S
通讯作者：
Kawanishi, S