Survivin is a bifunctional protein that plays crucial roles in tumorigenesis. In the present study, we discovered that the natural product gastrodin suppressed the cell viability and colony formation of non-small cell lung cancer (NSCLC) cell lines A549, HCC827, and H460 in a dose-dependent manner. In addition, gastrodin enhanced the protein levels of cleaved-caspase 3 by activating the endogenous mitochondrial apoptosis pathway. Gastrodin inhibits protein kinase B (Akt)/WEE1/cyclin-dependent kinase 1 (CDK1) signaling to downregulate survivin Thr34 phosphorylation. Survivin Thr34 dephosphorylation caused by gastrodin interfered with the binding of ubiquitin-specific protease 19 (USP19), which eventually destabilized survivin. We revealed that the growth of NSCLC xenograft tumors was markedly suppressed by gastrodin in vivo. Furthermore, gastrodin overcomes pemetrexed resistance in vivo or in vitro. Our results suggest that gastrodin is a potential antitumor agent by reducing survivin in NSCLC.
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