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Apatinib Promotes Ferroptosis in Colorectal Cancer Cells by Targeting ELOVL6/ACSL4 Signaling

Authors Tian X, Li S, Ge G

Received 15 August 2020

Accepted for publication 13 December 2020

Published 11 February 2021 Volume 2021:13 Pages 1333—1342

DOI https://doi.org/10.2147/CMAR.S274631

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 3

Editor who approved publication: Dr Chien-Feng Li


Xiangyang Tian,1 Shuyuan Li,2 Guoyan Ge2

1Department of Oncology, Peace Hospital, Changzhi Medical College, Changzhi, Shanxi Province, 046000, People’s Republic of China; 2Department of Tumor Spleen and Stomach, Hospital of Traditional Chinese Medicine of Changzhi City, Changzhi, Shanxi Province, 046013, People’s Republic of China

Correspondence: Xiangyang Tian
Peace Hospital, Changzhi Medical College, No. 110 Yan’an South Road, Luzhou District, Changzhi, Shanxi Province, 046000, People’s Republic of China
Email xiangyangd@163.com

Background: Colorectal cancer (CRC) is a common digestive system malignancy. Ferroptosis, a new form of regulated cell death, plays a vital role in the pathogenesis and therapy of cancers.
Objective: We aimed to study the role of apatinib in ferroptosis of CRC cells and its potential mechanisms.
Materials and Methods: Human CRC HCT116 cells were exposed to apatinib. Cell viability was examined using a CCK-8 kit. The concentrations of intracellular iron and reactive oxygen species (ROS) were detected using kits. Additionally, Western blot analysis was used to determine the expression of ferroptosis-related proteins. Elongation of very long-chain fatty acids family member 6 (ELOVL6) was one of the targets of apatinib predicted by SwissTargetPrediction. Therefore, ELOVL6 expression was evaluated after treatment with apatinib. Subsequently, the effects of ELOVL6 overexpression on ferroptosis of HCT116 cells were investigated. Finally, STRING database was applied to predict the potential proteins interacting with ELOVL6, and co-immunoprecipitation (co-IP) assay was applied for confirmation.
Results: Results indicated that apatinib decreased cell viability and increased the contents of intracellular iron ROS. Moreover, significantly upregulated ACSL4 expression was observed, accompanied by notable downregulation of GPx4 and FTH1 expression after apatinib exposure. Furthermore, ELOVL6 expression was remarkably enhanced in HCT116 cells, which was dramatically inhibited under apatinib intervention. ELOVL6 overexpression reversed the effects of apatinib on cell viability and ferroptosis of HCT116 cells. Moreover, ACSL4, a vital regulator of ferroptosis, could interact with ELOVL6 directly, which was confirmed by the result of co-IP.
Conclusion: These findings demonstrated that apatinib promoted ferroptosis in CRC cells by targeting ELOVL6/ACSL4, providing a new mechanism support for apatinib application in the clinical treatment of CRC.

Keywords: colorectal cancer, apatinib, ferroptosis, reactive oxygen species, ELOVL6

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