Autophagy inhibition potentiates the anti-angiogenic property of multikinase inhibitor anlotinib through JAK2/STAT3/VEGFA signaling in non-small cell lung cancer cells

被引：170

作者：

Liang, Lijun ^{[1
]}

Hui, Kaiyuan ^{[1
]}

Hu, Chenxi ^{[1
]}

Wen, Yixuan ^{[1
]}

Yang, Shikun ^{[2
,3
]}

Zhu, Panrong ^{[1
,4
]}

Wang, Lei ^{[1
]}

Xia, Youyou ^{[1
]}

Qiao, Yun ^{[1
]}

Sun, Wen ^{[1
]}

Fei, Jiayan ^{[1
]}

Chen, Ting ^{[1
]}

Zhao, Fenghua ^{[1
]}

Yang, Baocheng ^{[5
]}

Jiang, Xiaodong ^{[1
]}

机构：

[1] Xuzhou Med Univ, Affiliated Lianyungang Hosp, Dept Oncol, Lianyungang 222000, Jiangsu, Peoples R China

[2] Nanjing Med Univ, Affiliated Hosp 1, Hepatobiliary Liver Transplantat Ctr, Nanjing 210029, Jiangsu, Peoples R China

[3] Natl Hlth & Family Planning Commiss China, Key Lab Living Donor Liver Transplantat, Nanjing 210029, Jiangsu, Peoples R China

[4] Xuzhou Med Univ, Affiliated Hosp 2, Dept Radiol 3, Gen Hosp,Xuzhou Coal Min Grp, Xuzhou 221002, Jiangsu, Peoples R China

[5] Xuzhou Med Univ, Jiangsu Prov Inst Hlth Emergency, Xuzhou 221002, Jiangsu, Peoples R China

来源：

JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH | 2019年 / 38卷 / 1期

基金：

中国国家自然科学基金;

关键词：

Anlotinib; Autophagy; NSCLC; Apoptosis; Anti-angiogenesis; VEGFA; PATHWAY; GROWTH; TARGET; MTOR; AXIS;

D O I：

10.1186/s13046-019-1093-3

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Background: The efficacy and safety of multikinase inhibitor anlotinib have been confirmed in the treatment of advanced non-small cell lung cancer (NSCLC). However, the direct functional mechanisms of tumor lethality mediated by anlotinib were not fully elucidated, and the underlying mechanisms related to resistance remain largely elusive. Methods: Cell viability, colony formation, apoptosis and tumor growth assays were performed to examine the effect of anlotinib on lung cancer cells in vitro and in vivo. The punctate patterns of LC3-I/II were detected by confocal microscopy. HUVECs motility was detected using Transwell and scratch wound-healing assay. To visualize the microvessels, tubular formation assay was performed. The expression of LC3-I/II and beclin-1 and the changes of JAK2/STAT3/VEGFA pathway were detected by western blotting. The VEGFA levels in tumor supernatant were measured by ELISA. Results: Anlotinib treatment decreased cell viability and induced apoptosis in Calu-1 and A549 cells. Moreover, anlotinib induced human lung cancer cell autophagy in a dose- and time-dependent manner. Blocking autophagy enhanced the cytotoxicity and anti-angiogenic ability of anlotinib as evidenced by HUVECs migration, invasion, and tubular formation assay. Co-administration of anlotinib and chloroquine (CQ) further reduced VEGFA level in the tumor supernatant, compared with that of anlotinib or CQ treatment alone. When autophagy was induced by rapamycin, the JAK2/STAT3 pathway was activated and VEGFA was elevated, which was attenuated after deactivating STAT3 by S3I-201. Further in vivo studies showed that anlotinib inhibited tumor growth, induced autophagy and suppressed JAK2/STAT3/VEGFA pathway, and CQ enhanced this effect. Conclusion: Anlotinib induced apoptosis and protective autophagy in human lung cancer cell lines. Autophagy inhibition further enhanced the cytotoxic effects of anlotinib, and potentiated the anti-angiogenic property of anlotinib through JAK2/STAT3/VEGFA signaling.

引用

页数：13

共 36 条

[31] Another way to die: autophagic programmed cell death [J].