Apatinib Inhibits Cell Proliferation and Induces Autophagy in Human Papillary Thyroid Carcinoma via the PI3K/Akt/mTOR Signaling Pathway

Abstract

<b>Background:</b> Patients with metastatic radioiodine-refractory papillary thyroid carcinoma (PTC) have limited treatment options and a poor prognosis. There is an urgent need to develop new drugs targeting PTC for clinical application. Apatinib, a novel small-molecule tyrosine kinase inhibitor (TKI), is highly selective for vascular endothelial growth factor receptor-2 (VEGFR2) and exhibits antitumor effects in a variety of solid tumors. Although apatinib has been shown to be safe and efficacious in radioiodine-refractory differentiated thyroid cancer, the mechanism underlying its antitumor effect is unclear. In this report, we explored the effects of apatinib on PTC <i>in vitro</i> and <i>in vivo</i>. <b>Methods:</b> VEGFR2 expression levels were evaluated by immunohistochemistry (IHC), qPCR, and western blotting (WB). The effects of apatinib on cell viability, colony formation, and migration in the Transwell assay were assessed <i>in vitro</i>, and its effect on tumor growth rate was assessed <i>in vivo</i>. In addition, the levels of proteins in signaling pathways were determined by WB. Finally, the autophagy level was assessed by WB, immunofluorescence (IF), and transmission electron microscopy. <b>Results:</b> We found that high VEGFR2 expression is associated with tumor size, T stage, and lymph node metastasis in patients with PTC and that apatinib inhibits PTC cell growth, promotes apoptosis, and induces cell cycle arrest through the PI3K/Akt/mTOR signaling pathway. Moreover, apatinib induces autophagy, and pharmacological inhibition of autophagy or small interfering RNA (siRNA)-mediated targeting of autophagy-associated gene 5 (ATG5) can further increase PTC cell apoptosis. <b>Conclusion:</b> Our data suggest that apatinib can induce apoptosis and autophagy via the PI3K/Akt/mTOR signaling pathway for the treatment of PTC and that autophagy is a potential novel target for future therapy in resistant PTC.