Rapamycin is widely recognized as an inhibitor of mTOR, and has been approved for clinical use as an immunosuppressant. Its potencies in anti-cancer, anti-aging, and neurodegenerative diseases are emergingly established. The exploration of other targets of rapamycin will further elucidate its underlying mechanisms of action. In this study, we use a chemical proteomics strategy that has identified STAT3, a transcription factor considered to be undruggable, as a direct functional protein target of rapamycin. Together with other multi-dimensional proteomics data, we show that rapamycin treatment in cell culture significantly inhibits c-Myc-regulated gene expression. Furthermore, we show that rapamycin suppresses tumor growth along with a decreased expression of STAT3 and c-Myc in an in vivo xenograft mouse model for hepatocellular carcinoma. Our data suggest that rapamycin acts directly on STAT3 to decrease its transcription activity, providing important information for the pharmacological and pharmaceutical development of STAT3 inhibitors for cancer therapy.

雷帕霉素被广泛认为是mTOR的抑制剂，并已被批准作为免疫抑制剂用于临床。它在抗癌、抗衰老和神经退行性疾病方面的效力正在逐渐确立。对雷帕霉素其他靶点的探索将进一步阐明其潜在的作用机制。在这项研究中，我们使用一种化学蛋白质组学策略，该策略已将 STAT3（一种被认为不可成药的转录因子）鉴定为雷帕霉素的直接功能蛋白靶标。与其他多维蛋白质组学数据一起，我们表明细胞培养中的雷帕霉素处理显着抑制了 c-Myc 调节的基因表达。此外，我们发现雷帕霉素在体内抑制肿瘤生长，同时降低 STAT3 和 c-Myc 的表达。肝细胞癌的异种移植小鼠模型。我们的数据表明，雷帕霉素直接作用于 STAT3 以降低其转录活性，为 STAT3 抑制剂用于癌症治疗的药理学和药物开发提供重要信息。