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

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

doi:10.3389/fonc.2020.00217

Cited by 40 publications

(34 citation statements)

References 25 publications

(26 reference statements)

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“…In order to investigate the potential mechanism underlying the effect of apatinib, the study further analyzed the apatinibtreated cells and xenograft tumor tissues. The results revealed a decrease in the expression of p-ERK1/2 and p-AKT consistent with their behavior in thyroid cancer (27), gastric cancer (28), ovarian cancer (29), cholangiocarcinoma (22) and neuroblastoma (30). Previous research also showed that KRAS mutations appeared in 90% of pancreatic cancer patients (31), while RAS-stimulated ERK1/2/MAPK and PI3K/AKT were reported to be active in various pancreatic cancer models (32).…”

Section: Discussionsupporting

confidence: 66%

Apatinib inhibits pancreatic cancer growth, migration and invasion through the PI3K/AKT and ERK1/2/MAPK pathways

Hu¹,

Jing²,

Shi³

et al. 2021

Transl Cancer Res TCR

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Background: Pancreatic cancer is generally characterized with high levels of malignancy and poor prognosis. In addition, there are currently no effective therapeutic agents against the disease. However, apatinib which is a small molecular agent targeting the vascular endothelial growth factor receptor 2 (VEGFR-2), has been shown to generate favorable outcomes in gastric cancer. Therefore, the present study explored the effects of apatinib on pancreatic cancer. Methods:The activity of the ASPC-1 or PANC-1 cells was examined through colony formation assays, wound healing experiments as well as the Transwell and Western blot (WB) analyses. Additionally, axenograft model was established by subcutaneously injecting the ASPC-1 cells into nude mice. Microvessel density (MVD) and Ki-67 expression were examined through immunohistochemistry (IHC) and WB analyses. Results:The findings showed that treatment with either 10 or 20 μM of apatinib led to a decrease in the proliferation, migration and invasion of ASPC-1 and PANC-1 cells. Additionally, apatinib significantly hindered xenograft growth. Moreover, there was a decrease in Ki-67 expression and MVD, 21 days after treatment with apatinib. The results also showed that apatinib had no effect on the levels of the VEGFR-2, ERK1/2 and AKT proteins although there was a significant decrease in the expression of phosphate VEGFR2 (p-VEGFR2), phosphate AKT (p-AKT) and phosphate ERK1/2 (p-ERK1/2).Conclusions: Apatinib inhibits the proliferation and migration of pancreatic cancer cells, blocking growth and angiogenesis in transplanted tumors. In addition, the underlying mechanism may involve phosphorylation of the PI3K/AKT and ERK1/2/MAPKs signaling pathways.

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Section: Discussionsupporting

confidence: 66%

Apatinib inhibits pancreatic cancer growth, migration and invasion through the PI3K/AKT and ERK1/2/MAPK pathways

Hu¹,

Jing²,

Shi³

et al. 2021

Transl Cancer Res TCR

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“…Moreover, some novel drugs were utilized to TC therapy. For example, apatinib could induce apoptosis and autophagy of PTC cells through PI3K/Akt/ mTOR signaling pathway [60]. Previous studies have indicated that emodin inhibited the angiogenesis and metastasis of ATC by regulating TRAF6-mediated pathways, including the TRAF6/CD147/MMP9 pathway [47].…”

Section: Discussionmentioning

confidence: 99%

Immunohistochemical basigin expression level in thyroid cancer tissues

et al. 2020

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Background: Thyroid cancer (TC) is the most common endocrine malignancy; basigin (also known as BSG) plays a crucial role in tumor cell invasion, metastasis, and angiogenesis. This study was designed to identify the change of BSG expression in TC and its possible potential mechanism. Methods: The BSG expression levels in TC were demonstrated using data collected from in-house immunohistochemical (IHC), RNA-sequencing (RNA-seq), microarrays, and literatures. Integrated analysis was performed to determined BSG expression levels in TC comprehensively. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed with the integration of BSG co-expressed genes and differentially expressed genes (DEGs) in TC tissues to explore the potential mechanisms of BSG in TC. Results: The protein expression level of BSG was significantly higher in TC cases based on the IHC experiments. In addition, the combined SMD for BSG expression was 0.39 (p < 0.0001), the diagnostic odds ratio was 3.69, and the AUC of the sROC curve was 0.6986 using 1182 TC cases and 437 non-cancerous cases from 17 independent datasets. Furthermore, BSG co-expressed genes tended to be enriched in gene terms of the extracellular matrix (ECM), cell adhesion, and cell-cell interactions. The expression levels of nine hub BSG co-expressed genes were markedly upregulated in TC cases. Conclusion: BSG expression levels were closely correlated with the progression of TC and may affect the signals of the ECM, cell adhesion, and cell-cell interactions.

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“…Huang et al reported that apatinib inhibited the proliferation, migration and invasion of cholangiocarcinoma cells [ 35 ]. Meng et al found that apatinib inhibited cell proliferation and induced autophagy in human papillary thyroid carcinoma [ 36 ]. Xu et al proved that apatinib enhanced the chemosensitivity of gastric cancer cells to paclitaxel and 5-fluorouracil [ 37 ].…”

Section: Discussionmentioning

confidence: 99%

Apatinib induces endoplasmic reticulum stress-mediated apoptosis and autophagy and potentiates cell sensitivity to paclitaxel via the IRE-1α–AKT–mTOR pathway in esophageal squamous cell carcinoma

Wang

Tang

et al. 2021

Cell Biosci

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Background Apatinib, a novel vascular endothelial growth factor receptor-2 (VEGFR-2) tyrosine kinase inhibitor, has been approved for the treatment of metastatic gastric cancer and other tumors. Apatinib exerts antiproliferative and proapoptotic effects in different kinds of cancer cells. However, the molecular mechanisms by which apatinib effective against esophageal squamous cell carcinoma (ESCC) have only been partially researched and whether it has a sensitizing effect on paclitaxel remains unclear. Materials and methods The effects of apatinib or paclitaxel on endoplasmic reticulum (ER) stress, autophagy, apoptosis and proliferation of ESCC cell lines were evaluated. Western blot and immunohistochemistry analyses were performed to detect the expression of related genes. The weight and volume of xenograft tumors in mice were measured. Results In the current study, we elucidated the antiproliferative and ER-stress-mediated autophagy-inducing effects of apatinib on ECA-109 and KYSE-150 esophageal squamous cancer cells and identified the underlying mechanisms of its action. We demonstrated that apatinib not only inhibited the proliferation and induced the apoptosis of ESCC cells, but also activated ER stress and triggered protective autophagy. Moreover, inhibiting autophagy by chloroquine (CQ) enhanced the apatinib-induced apoptosis of ESCC cells through the IRE-1α–AKT–mTOR pathway. In addition, we showed, for the first time, the paclitaxel combined with apatinib and CQ exhibited the best antitumor effect on ESCC both in vivo and in vitro via the IRE-1α–AKT–mTOR pathway. Conclusions Our data showed that apatinib induced ER stress, autophagy and apoptosis in ESCC. Inhibiting autophagy by CQ enhanced apatinib-induced apoptosis. The combination of apatinib and CQ sensitized ESCC cells to paclitaxel to induce apoptosis through the IRE-1α–AKT–mTOR signaling pathway, thus providing the basis for its use in innovative anticancer therapeutic strategies. Graphic abstract

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

Cited by 40 publications

References 25 publications

Apatinib inhibits pancreatic cancer growth, migration and invasion through the PI3K/AKT and ERK1/2/MAPK pathways

Apatinib inhibits pancreatic cancer growth, migration and invasion through the PI3K/AKT and ERK1/2/MAPK pathways

Immunohistochemical basigin expression level in thyroid cancer tissues

Apatinib induces endoplasmic reticulum stress-mediated apoptosis and autophagy and potentiates cell sensitivity to paclitaxel via the IRE-1α–AKT–mTOR pathway in esophageal squamous cell carcinoma

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