Non-small cell lung cancer (NSCLC) accounts for more than 85% of lung cancer with high incidence and mortality. Accumulating studies have shown that traditional Chinese medicine (TCM) and its active ingredients have good anti-tumor activity. However, the anti-tumor effect of Thevebioside (THB), an active ingredient from TCM, is still unknown in NSCLC. In this study, to our best knowledge, it was the first time to report the underlying mechanism of its tumor-suppressive activity in NSCLC based on our previous high-throughput screening data. We further demonstrated that THB effectively inhibited the proliferation of NSCLC cells (A549 and H460) by inducing cellular apoptosis rather than cell cycle arrest. Notably, it was demonstrated that SRC-3 was significantly down-regulated after THB treatment dependent on ubiquitin-proteasome-mediated degradation, which subsequently inhibited the IGF-1R–PI3K-AKT signaling pathway and promoted apoptosis via both in vivo and in vitro experiments. Collectively, THB exerted inhibitory effect on tumor growth of NSCLC through inhibiting SRC-3 mediated IGF-1R–PI3K-AKT signaling by ubiquitination to induce cellular apoptosis with minimal toxicity no matter in vitro or vivo.

非小细胞肺癌（NSCLC）占高发病率和高死亡率的肺癌的85％以上。越来越多的研究表明，中药（TCM）及其有效成分具有良好的抗肿瘤活性。然而，非小细胞肺癌中的活性成分Thevebioside（THB）的抗肿瘤作用仍然未知。在本研究中，就我们所知，这是首次基于我们以前的高通量筛选数据报告其在NSCLC中抑癌活性的潜在机制。我们进一步证明了THB通过诱导细胞凋亡而不是细胞周期停滞有效地抑制了NSCLC细胞（A549和H460）的增殖。值得注意的是，已证明THB处理后SRC-3的表达明显下调，这取决于泛素-蛋白酶体介导的降解，随后通过体内和体外实验抑制了IGF-1R–PI3K-AKT信号通路并促进了细胞凋亡。总的来说，THB通过泛素化抑制SRC-3介导的IGF-1R–PI3K-AKT信号转导，从而诱导NSCLC的肿瘤生长，无论在体内还是体外均具有最小的毒性。