Monin, Malte B. and Krause, Petra and Stelling, Robin and Bocuk, Derya and Niebert, Sabine and Klemm, Florian and Pukrop, Tobias and Koenig, Sarah (2016) The anthelmintic niclosamide inhibits colorectal cancer cell lines via modulation of the canonical and noncanonical Wnt signaling pathway. JOURNAL OF SURGICAL RESEARCH, 203 (1). pp. 193-205. ISSN 0022-4804, 1095-8673
Full text not available from this repository. (Request a copy)Abstract
Background: Wnt/beta-catenin signaling is known to play an important role in colorectal cancer (CRC). Niclosamide, a salicylamide derivative used in the treatment of tapeworm infections, targets the Wnt/beta-catenin pathway. The objective of this study was to investigate niclosamide as a therapeutic agent against CRC. Methods: The antiproliferative effects of 1, 3, 10, and 50 mu M concentrations of niclosamide on human (SW480 and SW620) and rodent (CC531) CRC cell lines were determined by MTS assay and direct cell count. The lymphoid enhancer-binding factor 1/transcription factor (LEF/TCF) reporter assay monitored the activity of Wnt signaling. Immunofluorescence staining demonstrated the expression pattern of active beta-catenin. Gene expression of canonical and noncanonical Wnt signaling components was analyzed using qRT-PCR. Western blot analysis was performed with antibodies detecting nuclear localization of beta-catenin and c-jun. Results: Cell proliferation in CRC cell lines was blocked dose dependently after 12 and 24 h of incubation. The Wnt promoter activity of LEF/TCF significantly decreased with niclosamide concentrations of 10 and 50 mM after 12 h of incubation. Active beta-catenin did not shift from the nuclear to the cytosolic pool. However, canonical target genes (met, MMP7, and cyclin D1) as well as the coactivating factor Bcl9 were downregulated, whereas the noncanonical key player c-jun was clearly activated. Conclusions: Niclosamide treatment is associated with an inhibitory effect on CRC development and reduced Wnt activity. It may exert its effect by interfering with the nuclear beta-catenin-Bcl9-LEF/TCF triple-complex and by upregulation of c-jun representing noncanonical Wnt/JNK signaling. Thus, our findings warrant further research into this substance as a treatment option for patients with advanced CRC. (C) 2016 Elsevier Inc. All rights reserved.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | BETA-CATENIN; COLON-CANCER; ADENOMATOUS POLYPOSIS; REGULATES EXPRESSION; STEM-CELLS; CYCLIN D1; COMPLEX; TARGET; APC; PROGRESSION; Niclosamide; Drug repositioning; CRC cell lines; Inhibition of canonical and noncanonical Wnt signaling; Selective chemotherapeutic efficacy |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Innere Medizin III (Hämatologie und Internistische Onkologie) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 01 Mar 2019 13:09 |
| Last Modified: | 12 Mar 2019 06:17 |
| URI: | https://pred.uni-regensburg.de/id/eprint/2841 |
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