Thevebioside, the active ingredient of traditional Chinese medicine, promotes ubiquitin-mediated SRC-3 degradation to induce NSCLC cells apoptosis

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.