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FL118 inhibits viability and induces apoptosis of colorectal cancer cells via inactivating the CIP2A/PP2A axis.

Authors
  • Lin, Xuezhu1
  • Gao, Mingquan2
  • Zhang, Ailing3
  • Tong, Jingjie4
  • Zhang, Xiaoyi1
  • Su, Quanzhong1
  • Yang, Zhihong1
  • Gao, Hui5
  • Jiang, Guohui6
  • 1 Department of Pharmacology, School of Pharmacy, Qingdao University, Qingdao 266021, Shandong Province, China. , (China)
  • 2 Qingdao Hiser hospital, Qingdao 266033, Shandong Province, China. , (China)
  • 3 Department of school infirmary, Qingdao University, Qingdao 266021, Shandong Province, China. , (China)
  • 4 Sichuan Cancer Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610041, Sichuan Province, China. , (China)
  • 5 Department of Pharmacology, School of Pharmacy, Qingdao University, Qingdao 266021, Shandong Province, China. Electronic address: [email protected] , (China)
  • 6 Department of Pharmacology, School of Pharmacy, Qingdao University, Qingdao 266021, Shandong Province, China. Electronic address: [email protected] , (China)
Type
Published Article
Journal
Life sciences
Publication Date
Dec 15, 2019
Volume
239
Pages
117074–117074
Identifiers
DOI: 10.1016/j.lfs.2019.117074
PMID: 31751585
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

FL118, a novel camptothecin analogue, has been extensively studied for its superior antitumor potency. The aim of this research study is to explore its potential mechanism of action in anti- colorectal cancer (CRC). The effect of FL118 on CRC cell proliferation was assessed using CCK-8 assay, while apoptosis was detected using Hoechst staining and Flow cytometry assays. The expression levels of CIP2A were analyzed using qRT-PCR. The expression of CIP2A, PP2A-C, Bax, cleaved caspase-3 and PARP were analyzed using western blotting analysis. The expressions of related proteins in CRC tissues were detected using immunohistochemical staining. TUNEL assay was used to detect apoptosis of tissue. Toxicity of FL118 in primary organs were examined using H&E staining. The results show that FL118 can inhibit the proliferation and clonogenic potential of CRC cells and increase the expression of pro-apoptosis proteins, Bax, cleaved caspase-3 and PARP. Microarray analyses found that FL118 treatment significantly decreases cancerous inhibition of protein phosphatase 2A (CIP2A). Further validation found that CIP2A is aberrantly upregulated in CRC tissues, and is positively correlated with the progression of CRC. In vitro findings confirm that FL118 mediates the downregulation of CIP2A, at both protein and mRNA levels. Co-treatment with Okadaic acid (OA) (a PP2A inhibitor) partially abolishes the anti-proliferative and pro-apoptotic effect of FL118. Consistently, in vivo experiment demonstrates that FL118 can effectively suppress tumorigenesis without any obvious toxic effects. Collectively, these findings exhibit the anti-neoplastic effects of FL118 against CRC through the down regulation of CIP2A, which subsequently enhances the activity of PP2A. Copyright © 2019 Elsevier Inc. All rights reserved.

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