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Molecules 2018, 23(9), 2264; https://doi.org/10.3390/molecules23092264

Involvement of Up-Regulation of DR5 Expression and Down-Regulation of c-FLIP in Niclosamide-Mediated TRAIL Sensitization in Human Renal Carcinoma Caki Cells

1
Department of Immunology, School of Medicine, Keimyung University, 1095 Dalgubeoldaero, Dalseo-Gu, Daegu 42601, Korea
2
Department of Otolaryngology, School of Medicine, Keimyung University, 1095 Dalgubeoldaero, Dalseo-Gu, Daegu 42601, Korea
*
Author to whom correspondence should be addressed.
Received: 17 August 2018 / Revised: 3 September 2018 / Accepted: 3 September 2018 / Published: 5 September 2018
(This article belongs to the Section Chemical Biology)
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Abstract

Niclosamide is used to treat intestinal parasite infections, as being an anthelmintic drug. Recently, several papers suggest the niclosamide inhibits multiple signaling pathways, which are highly activated and mutated in cancer. Here, niclosamide was evaluated for identifying strategies to overcome tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) resistance. Although niclosamide (100–200 nM) alone did not bring about cell death, combinations of niclosamide and TRAIL led to apoptotic cell death in carcinoma cells, but not in normal cells. Niclosamide markedly increased DR5 protein levels, including cell-surface DR5, and decreased c-FLIP protein levels. Down-regulation of DR5 by specific small interfering RNA (siRNA) and ectopic expression of c-FLIP markedly blocked niclosamide plus TRAIL-induced apoptosis. Our findings provide that niclosamide could overcome resistance to TRAIL through up-regulating DR5 on the cell surface and down-regulating c-FLIP in cancer cells. Taken together, niclosamide may be an attractive candidate to overcome TRAIL resistance. View Full-Text
Keywords: niclosamide; TRAIL; DR5; c-FLIP; apoptosis niclosamide; TRAIL; DR5; c-FLIP; apoptosis
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).
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Yun, J.M.; Woo, S.M.; Seo, S.U.; Min, K.-J.; Kim, D.E.; Kwon, T.K. Involvement of Up-Regulation of DR5 Expression and Down-Regulation of c-FLIP in Niclosamide-Mediated TRAIL Sensitization in Human Renal Carcinoma Caki Cells. Molecules 2018, 23, 2264.

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