AUTHOR=Meng Xiangrui , Wang Huijuan , Zhao Jingzhu , Hu Linfei , Zhi Jingtai , Wei Songfeng , Ruan Xianhui , Hou Xiukun , Li Dapeng , Zhang Jun , Yang Weiwei , Qian Biyun , Wu Yu , Zhang Yuan , Meng Zhaowei , Guan Lizhao , Zhang Huilai , Zheng Xiangqian , Gao Ming 

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

JOURNAL=Frontiers in Oncology

VOLUME=10

YEAR=2020

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2020.00217

DOI=10.3389/fonc.2020.00217

ISSN=2234-943X

ABSTRACT=<p><bold>Background:</bold> 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 <italic>in vitro</italic> and <italic>in vivo</italic>.</p><p><bold>Methods:</bold> 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 <italic>in vitro</italic>, and its effect on tumor growth rate was assessed <italic>in vivo</italic>. 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.</p><p><bold>Results:</bold> 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.</p><p><bold>Conclusion:</bold> 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.</p>