Apatinib affect VEGF-mediated cell proliferation, migration, invasion via blocking VEGFR2/RAF/MEK/ERK and PI3K/AKT pathways in cholangiocarcinoma cell

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Abstract

Background

Cholangiocarcinoma (CCA) is a form of cancer that easily aggress to contiguous structures. Vascular endothelial growth factor (VEGF) and VEGF receptor 2 (VEGFR2) are increased in majority species of cancers and suppress tumor progression by blocking VEGF/VEGFR2. Apatinib is a highly selective VEGFR2 antagonist which has inhibitive effect on antiapoptotic and cell growth in CCA. While, the effect of apatinib cell migration and invasion in CCA is still unknown.

Methods

CCA cell lines QBC939 and TFK-1 were transfected with siKDR to establish the KDR function loss cell model, and recombined human VEGF (rhVEGF) protein was added into the culture medium to enhance the VEGF expression. RT-qPCR and western bloting were used to detect the mRNA and protein expression levels of VEGFR2 to investigate whether it was effectively repressed or activated with rhVEGF or apatinib treatment. Then, MTT, wound healing assay, and transwell matrix assay were applied to measure the effect of apatinib and rhVEGF on cell viability, migration and invasion, respectively.

Results

The mRNA and protein expressions of VEGFR2 were significantly reduced with KDR RNAi in both QBC939 and TFK-1 cells, and rhVEGF treatment increased these expression levels ( p < 0.05). Apatinib dramatically suppressed VEGF-mediated cell migration and invasion at the concentration of 100 nM treatment and significantly decreased the expression of metastasis-associated protein such as Slug, snail and MMP9. Moreover, all of these inhibiting effects of apatinib depended on the VEGFR2 existence. In addition, VEGFR2/RAF/MEK/ERK and PI3K/AKT signal pathways were enhanced by the introduction of rhVEGF, but were dramatically suppressed after the apatinib treatment.

Conclusion

Apatinib inhibit VEGF-mediated cell migration and invasion in CCA cell lines via inhibiting the VEGFR2/RAF/MEK/ERK and PI3K/AKT pathways. It will be a potentially effective targeted drug for CCA.

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Most cited references 27

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Cholangiocarcinoma: thirty-one-year experience with 564 patients at a single institution.

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To assess long-term survival and prognostic factors in a large series of patients with bile duct cancer. The incidence of bile duct cancer is low but increasing. Determinants of survival vary in the literature, due to a lack of sufficient numbers of patients in most series. We studied 564 consecutive patients with bile duct cancer operated upon between 1973 and 2004. Patients were divided into intrahepatic, perihilar, and distal groups. Principle outcome measures were complications, 30-day mortality, and survival. Of the 564 patients, 44 (8%) had intrahepatic, 281 (50%) had perihilar, and 239 (42%) had distal tumors. Approximately half (294, 52%) were treated before 1995, while 270 (48%) were treated thereafter. The perioperative mortality rate was 4%. In log-rank analyses, survival was higher in the later time period (P = 0.002), in patients with intrahepatic disease (P = 0.001), with negative resection margins (P < 0.001), with well/moderately differentiated tumors (P < 0.001), and those with negative lymph nodal status (P < 0.001). In multivariate analysis, negative margins (P < 0.001), tumor differentiation (P < 0.001), and negative nodal status (P < 0.001), but not tumor diameter, were significant independent prognostic factors. In R0-resected patients, lymph node status (P < 0.001), but not tumor diameter, histology, or differentiation, further predicted survival. The median survivals for R0-resected intrahepatic, perihilar, and distal tumors were 80, 30, and 25 months, respectively, and the 5-year survivals were 63%, 30%, and 27%, respectively. R0 resection remains the best chance for long-term survival, and lymph node status is the most important prognostic factor following R0 resection.

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Tumor ascites fluids from guinea pigs, hamsters, and mice contain activity that rapidly increases microvascular permeability. Similar activity is also secreted by these tumor cells and a variety of other tumor cell lines in vitro. The permeability-increasing activity purified from either the culture medium or ascites fluid of one tumor, the guinea pig line 10 hepatocarcinoma, is a 34,000- to 42,000-dalton protein distinct from other known permeability factors.

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YN968D1 is a novel and selective inhibitor of vascular endothelial growth factor receptor-2 tyrosine kinase with potent activity in vitro and in vivo.

Shu Tian, Haitian Quan, Chengying Xie … (2011)

Angiogenesis is an important process in cell development, especially in cancer. Vascular endothelial growth factor (VEGF) signaling is an important regulator of angiogenesis. Several therapies that act against VEGF signal transduction have been developed, including YN968D1, which is a potent inhibitor of the VEGF signaling pathway. This study investigated the antitumor activity of YN968D1 (apatinib mesylate) in vitro and in vivo. YN968D1 potently suppressed the kinase activities of VEGFR-2, c-kit and c-src, and inhibited cellular phosphorylation of VEGFR-2, c-kit and PDGFRβ. YN968D1 effectively inhibited proliferation, migration and tube formation of human umbilical vein endothelial cells induced by FBS, and blocked the budding of rat aortic ring. In vivo, YN968D1 alone and in combination with chemotherapeutic agents effectively inhibited the growth of several established human tumor xenograft models with little toxicity. A phase I study of YN968D1 has shown encouraging antitumor activity and a manageable toxicity profile. These findings suggest that YN968D1 has promise as an antitumor drug and might have clinical benefits. © 2011 Japanese Cancer Association.

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Author and article information

Contributors

Manping Huang: huangmanping1121@sina.com

Bin Huang: huangbin20171121@sina.com

Guowen Li: liguowen1121@sina.com

Sainan Zeng: +86-0731-88638888 , zengsainan1121@163.com

Journal

Journal ID (nlm-ta): BMC Gastroenterol

Journal ID (iso-abbrev): BMC Gastroenterol

Title: BMC Gastroenterology

Publisher: BioMed Central (London )

ISSN (Electronic): 1471-230X

Publication date (Electronic): 6 November 2018

Publication date PMC-release: 6 November 2018

Publication date Collection: 2018

Volume: 18

Electronic Location Identifier: 169

Affiliations

[1 ]GRID grid.410622.3, Department of Intervention, , Hunan Cancer Hospital & The Affiliated Cancer Hospital of Xiangya School of Medicine, Central SouthUniversity, ; No.283 , Tongzipo Road, Changsha, 410013 People’s Republic of China

[2 ]GRID grid.431010.7, Infection Controlling Center, , The Third Xiangya Hospital of Central South University, ; Tongzipo Road, Yuelu District, Changsha, 410013 People’s Republic of China

Article

Publisher ID: 870

DOI: 10.1186/s12876-018-0870-3

PMC ID: 6220519

PubMed ID: 30400838

SO-VID: 65f39283-f4e5-49f5-b6be-00c76d00029c

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 7 December 2017

Date accepted : 10 September 2018

Custom metadata

ScienceOpen disciplines: Gastroenterology & Hepatology

Keywords: cholangiocarcinoma,apatinib,vegf,kdr (vegfr2),raf/mek/erk pathway,pi3k/akt pathway

Data availability:

ScienceOpen disciplines: Gastroenterology & Hepatology

Keywords: cholangiocarcinoma, apatinib, vegf, kdr (vegfr2), raf/mek/erk pathway, pi3k/akt pathway

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Apatinib affect VEGF-mediated cell proliferation, migration, invasion via blocking VEGFR2/RAF/MEK/ERK and PI3K/AKT pathways in cholangiocarcinoma cell

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Abstract

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Karger: Gastroenterology

Most cited references 27

Cholangiocarcinoma: thirty-one-year experience with 564 patients at a single institution.

Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid

YN968D1 is a novel and selective inhibitor of vascular endothelial growth factor receptor-2 tyrosine kinase with potent activity in vitro and in vivo.

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