Apatinib Inhibits Angiogenesis Via Suppressing Akt/GSK3β/ANG Signaling Pathway in Anaplastic Thyroid Cancer

Jin, Zhijian; Cheng, Xi; Feng, Haoran; Kuang, Jie; Yang, Weiping; Peng, Chenghong; Shen, Baiyong; Qiu, Weihua

doi:10.1159/000485583

Cited by 53 publications

(57 citation statements)

References 42 publications

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“…Apatinib was reported to suppress angiogenesis in anaplastic thyroid carcinoma by blocking the Akt/GSK3/ANG pathway (20)(21)(22); however, the effect of apatinib in PTC is unclear. In this report, we discovered that apatinib could inhibit PTC cell growth and migration and the induction of apoptosis.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2020

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Background: 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 in vitro and in vivo.Methods: 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 in vitro, and its effect on tumor growth rate was assessed in vivo. 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.Results: 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.Meng et al. Effects of Apatinib in PTCConclusion: 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.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2020

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“…However, the complexity in molecular subtypes of PTCs is still a challenge in exploring novel biomarker for guiding personal treatment in advanced stage (9). Meanwhile, alterations of critical signaling pathways in thyroid development like MAPK and PI3K-AKT can initiate tumorigenesis and promote tumor metastasis (10). Targeting the aberrant expression of development related genes or signaling may provide an opportunity for the molecular-based treatment of thyroid cancer.…”

Section: Introductionmentioning

confidence: 99%

SIX1 Activates STAT3 Signaling to Promote the Proliferation of Thyroid Carcinoma via EYA1

Kong

Liu

et al. 2019

Front. Oncol.

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As a critical member of the Retinal Determination Gene Network (RDGN), SIX1 has been regarded as a tumor promoter in various types of cancer. However, its role in papillary thyroid carcinoma (PTC) has never been investigated. In this study, thyroid carcinoma tissue microarray staining was employed to identify the expression patterns of SIX1 and its co-activator EYA1. Papillary thyroid cancer cell lines, BCPAP, and TPC-1 cells were used to investigate the potential mechanism of SIX1 in vitro and in vivo. Flow cytometry analysis, MTT assay, the growth curve assay, colony formation assay, EdU incorporation and xenograft assay were performed to demonstrate the role of SIX1 in the malignant change of PTC cells. Western blot and Real-time PCR were used to detect the interaction among the SIX1, EYA1, and STAT3 signaling. In comparison with normal tissue, high expressions of SIX1 and EYA1 were associated with a malignant tumor. Importantly, SIX1 strongly correlated with EYA1 in thyroid carcinoma tissue microarray. Functional assays indicated SIX1 increased EYA1 expression by stabilizing EYA1 at the post-transcriptional level. Besides, SIX1 promoted the proliferation and invasion of thyroid carcinoma via activation of STAT3 signaling and its downstream targets in an EYA1-dependent manner. SIX1 can integrate with EYA1 to contribute to PTC development via activation of the classical STAT3 signaling. These data suggested targeting the abnormal activation of the SIX1/EYA1 complex may represent a novel therapeutic strategy for advanced PTC patients.

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“…It has been approved by the China Food and Drug Administration as a subsequent‐line treatment for advanced gastric or gastric‐esophageal junction adenocarcinoma. In addition, apatinib hepatocellular carcinoma, metastatic knot rectal cancer, thyroid undifferentiated carcinoma and other malignant tumors have shown good results . Studies have confirmed that bevacizumab combined with chemotherapy is more effective than a single drug, while the efficacy and side effects of apatinib combined with other drugs are unclear.…”

Section: Introductionmentioning

confidence: 99%

The effect of apatinib combined with chemotherapy or targeted therapy on non‐small cell lung cancer in vitro and vivo

Liu

Wang

et al. 2019

Thoracic Cancer

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Background The aim of this study was to investigate the feasibility of using a combination of apatinib in the treatment of non‐small cell lung cancer. Apatinib is a tyrosine kinase inhibitor which selectivelyacts on vascular endothelial growth factor receptor 2 (VEGFR‐2) and has shown good efficacy in a variety of malignancies, but the drug resistance is fast in single drug therapy. Methods The inhibitory effect of apatinib and other drugs on lung cancer cells was determined by CCK‐8 test in vitro, and the IC50 value was determined. To establish a nude mouse xenograft model, observe the inhibitory effect of apatinib combined with other drugs on lung cancer xenografts in nude mice; immunohistochemical staining of tumor microvessel density and Ki67 expression in transplanted tumor tissues; Western blot analysis of related signaling pathways expression; immunohistochemistry was used to detect tumor microvessel density in other organs and to observe its safety. Results In this study, we found apatinib combined with pemetrexed, the first and third generation of epidermal growth factor receptor tyrosine kinase inhibitor, could synergistically inhibit the proliferation of non‐small cell lung cancer cell (NSCLC) lines, reduce the microvessel density and Ki67 protein levels of three non‐small cell lung cancer xenografts, and enhance anti‐tumor activity by synergistically inhibiting the MAPK‐ERK and PI3K‐AKT‐mTOR signaling pathway. Furthermore, there were no pathological abnormalities in the heart, brain, liver and kidney of each group. Conclusions The efficacy of apatinib combination is better than that of monotherapy, and there is no significant difference in toxicity of important organs, which suggests the feasibility of a combination of apatinib in the treatment of non‐small cell lung cancer.

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Apatinib Inhibits Angiogenesis Via Suppressing Akt/GSK3β/ANG Signaling Pathway in Anaplastic Thyroid Cancer

Cited by 53 publications

References 42 publications

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

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

SIX1 Activates STAT3 Signaling to Promote the Proliferation of Thyroid Carcinoma via EYA1

The effect of apatinib combined with chemotherapy or targeted therapy on non‐small cell lung cancer in vitro and vivo

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