Apatinib promotes autophagy and apoptosis through VEGFR2/STAT3/BCL-2 signaling in osteosarcoma.
Apatinib promotes autophagy and apoptosis through VEGFR2/STAT3/BCL-2 signaling in osteosarcoma.
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DOI：
10.1038/cddis.2017.422
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发表时间：
2017-08-24
影响因子：
9
通讯作者：
Guo W
中科院分区：
文献类型：
--
作者：
Liu K;Ren T;Huang Y;Sun K;Bao X;Wang S;Zheng B;Guo W
骨肉瘤的治愈率在过去的30年里没有提高。迫切需要寻找新的治疗方法和药物。阿帕替尼是一种高选择性的血管内皮生长因子受体2（VEGFR 2）酪氨酸激酶抑制剂，在多种肿瘤中显示出良好的抗肿瘤作用。阿帕替尼对人骨肉瘤的抗肿瘤作用未见报道。我们在体外和体内研究了阿帕替尼对骨肉瘤的作用。VEGF 2高表达的骨肉瘤患者预后差。阿帕替尼可抑制骨肉瘤细胞的生长。除了周期阻滞和细胞凋亡，阿帕替尼诱导自噬。有趣的是，抑制自噬增加了骨肉瘤细胞中阿帕替尼诱导的凋亡。免疫沉淀证实VEGFR 2与信号转导子和转录激活子3（STAT 3）之间的直接结合。通过siRNA下调VEGFR 2导致KHOS细胞中的STAT 3抑制。在KHOS细胞中，阿帕替尼抑制VEGFR 2和STAT 3，STAT 3在VEGFR 2下游起作用。阿帕替尼下调STAT 3和BCL-2表达。siRNA敲低STAT 3可增强阿帕替尼诱导的自噬和凋亡。BCL-2抑制自噬，Apatinib也抑制凋亡。BCL-2的过表达减少了阿帕替尼诱导的细胞凋亡和自噬。阿帕替尼可抑制STAT 3和BCL-2的表达，抑制骨肉瘤的生长。综上所述，VEGFR 2/STAT 3/BCL-2信号通路的失活导致阿帕替尼诱导的骨肉瘤生长抑制。
The cure rate of osteosarcoma has not improved in the past 30 years. The search for new treatments and drugs is urgently needed. Apatinib is a high selectivity inhibitor of vascular endothelial growth factor receptor-2 (VEGFR2) tyrosine kinase, exerting promising antitumoral effect in various tumors. The antitumor effect of Apatinib in human osteosarcoma has never been reported. We investigated the effects of Apatinib in osteosarcoma in vitro and in vivo. Osteosarcoma patients with high levels of VEGFR2 have poor prognosis. Apatinib can inhibit cell growth of osteosarcoma cells. In addition to cycle arrest and apoptosis, Apatinib induces autophagy. Interestingly, inhibition of autophagy increased Apatinib-induced apoptosis in osteosarcoma cells. Immunoprecipitation confirmed direct binding between VEGFR2 and signal transducer and activator of transcription 3 (STAT3). Downregulation of VEGFR2 by siRNA resulted in STAT3 inhibition in KHOS cells. VEGFR2 and STAT3 are inhibited by Apatinib in KHOS cells, and STAT3 act downstream of VEGFR2. STAT3 and BCL-2 were downregulated by Apatinib. STAT3 knockdown by siRNA reinforced autophagy and apoptosis induced by Apatinib. BCL-2 inhibits autophagy and was apoptosis restrained by Apatinib too. Overexpression of BCL-2 decreased Apatinib-induced apoptosis and autophagy. Apatinib repressed the expression of STAT3 and BCL-2 and suppressed the growth of osteosarcoma in vivo. To sum up, deactivation of VEGFR2/STAT3/BCL-2 signal pathway leads to Apatinib-induced growth inhibition of osteosarcoma.
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影响因子：
7.7
作者：
He C;Zhu H;Li H;Zou MH;Xie Z
通讯作者：
Xie Z
影响因子：
--
作者：
Peng QX;Han YW;Zhang YL;Hu J;Fan J;Fu SZ;Xu S;Wan Q
通讯作者：
Wan Q
DOI：
10.1186/s13046-015-0251-5
发表时间：
2015-11-02
期刊：
Journal of experimental & clinical cancer research : CR
影响因子：
--
作者：
Sevelda F;Mayr L;Kubista B;Lötsch D;van Schoonhoven S;Windhager R;Pirker C;Micksche M;Berger W
通讯作者：
Berger W
影响因子：
13.3
作者：
Morgan MJ;Gamez G;Menke C;Hernandez A;Thorburn J;Gidan F;Staskiewicz L;Morgan S;Cummings C;Maycotte P;Thorburn A
通讯作者：
Thorburn A
影响因子：
13.3
作者：
Akar, Ugur;Chaves-Reyez, Arturo;Ozpolat, Bulent
通讯作者：
Ozpolat, Bulent