PDF(Pubmed)
Abstract：
Non-small cell lung cancer (NSCLC), an aggressive subtype of pulmonary carcinomas with high mortality, accounts for 85% of all lung cancers. Drug resistance and high recurrence rates impede the chemotherapeutic effect, making it urgent to develop new anti-NSCLC agents. Recently, we have demonstrated that para-toluenesulfonamide is a potential anti-tumor agent in human castration-resistant prostate cancer (CRPC) through inhibition of Akt/mTOR/p70S6 kinase pathway and lipid raft disruption. In the current study, we further addressed the critical role of cholesterol-enriched membrane microdomain and autophagic activation to para-toluenesulfonamide action in killing NSCLC. Similar in CRPC, para-toluenesulfonamide inhibited the Akt/mTOR/p70S6K pathway in NSCLC cell lines NCI-H460 and A549, leading to G1 arrest of the cell cycle and apoptosis. Para-toluenesulfonamide significantly decreased the cholesterol levels of plasma membrane. External cholesterol supplement rescued para-toluenesulfonamide-mediated effects. Para-toluenesulfonamide induced a profound increase of LC3-II protein expression and a significant decrease of p62 expression. Double staining of lysosomes and cellular cholesterol showed para-toluenesulfonamide-induced lysosomal transportation of cholesterol, which was validated using flow cytometric analysis of lysosome staining. Moreover, autophagy inhibitors could blunt para-toluenesulfonamide-induced effect, indicating autophagy induction. In conclusion, the data suggest that para-toluenesulfonamide is an effective anticancer agent against NSCLC through G1 checkpoint arrest and apoptotic cell death. The disturbance of membrane cholesterol levels and autophagic activation may play a crucial role to para-toluenesulfonamide action.
摘要：
非小细胞肺癌（NSCLC），一种侵袭性高死亡率的肺癌亚型，占所有肺癌的85%。耐药性和高复发率阻碍了化疗效果，迫切需要开发新的抗NSCLC药物。最近,我们已经证明,对甲苯磺酰胺通过抑制Akt/mTOR/p70S6激酶通路和脂筏破坏,在人去势抵抗性前列腺癌(CRPC)中是一种潜在的抗肿瘤药物.在目前的研究中,我们进一步探讨了富含胆固醇的膜微结构域和自噬激活对对甲苯磺酰胺在杀伤NSCLC中的关键作用.类似于CRPC，对甲苯磺酰胺抑制NSCLC细胞系NCI-H460和A549中的Akt/mTOR/p70S6K途径,导致细胞周期G1阻滞和细胞凋亡。对甲苯磺酰胺可显着降低质膜胆固醇水平。外部胆固醇补充挽救了对甲苯磺酰胺介导的作用。对甲苯磺酰胺诱导LC3-II蛋白表达的显着增加和p62表达的显着降低。溶酶体和细胞胆固醇的双重染色显示对甲苯磺酰胺诱导的胆固醇溶酶体运输，使用溶酶体染色的流式细胞术分析进行了验证。此外，自噬抑制剂可以减弱对甲苯磺酰胺诱导的作用，表明自噬诱导。总之,数据表明,对甲苯磺酰胺是通过G1检查点阻滞和凋亡性细胞死亡对抗NSCLC的有效抗癌剂.膜胆固醇水平的紊乱和自噬激活可能对对甲苯磺酰胺的作用起关键作用。
