Involvement of Up-Regulation of DR5 Expression and Down-Regulation of c-FLIP in Niclosamide-Mediated TRAIL Sensitization in Human Renal Carcinoma Caki Cells
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...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2018-09-01
|
| Series: | Molecules |
| Subjects: | |
| Online Access: | http://www.mdpi.com/1420-3049/23/9/2264 |
| _version_ | 1818874271450005504 |
|---|---|
| author | Jeong Mi Yun Seon Min Woo Seung Un Seo Kyoung-Jin Min Dong Eun Kim Taeg Kyu Kwon |
| author_facet | Jeong Mi Yun Seon Min Woo Seung Un Seo Kyoung-Jin Min Dong Eun Kim Taeg Kyu Kwon |
| author_sort | Jeong Mi Yun |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-19T13:07:57Z |
| format | Article |
| id | doaj.art-f6368f783c3c4b479cca4c0cf6638d5a |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-12-19T13:07:57Z |
| publishDate | 2018-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-f6368f783c3c4b479cca4c0cf6638d5a2022-12-21T20:20:00ZengMDPI AGMolecules1420-30492018-09-01239226410.3390/molecules23092264molecules23092264Involvement of Up-Regulation of DR5 Expression and Down-Regulation of c-FLIP in Niclosamide-Mediated TRAIL Sensitization in Human Renal Carcinoma Caki CellsJeong Mi Yun0Seon Min Woo1Seung Un Seo2Kyoung-Jin Min3Dong Eun Kim4Taeg Kyu Kwon5Department of Immunology, School of Medicine, Keimyung University, 1095 Dalgubeoldaero, Dalseo-Gu, Daegu 42601, KoreaDepartment of Immunology, School of Medicine, Keimyung University, 1095 Dalgubeoldaero, Dalseo-Gu, Daegu 42601, KoreaDepartment of Immunology, School of Medicine, Keimyung University, 1095 Dalgubeoldaero, Dalseo-Gu, Daegu 42601, KoreaDepartment of Immunology, School of Medicine, Keimyung University, 1095 Dalgubeoldaero, Dalseo-Gu, Daegu 42601, KoreaDepartment of Otolaryngology, School of Medicine, Keimyung University, 1095 Dalgubeoldaero, Dalseo-Gu, Daegu 42601, KoreaDepartment of Immunology, School of Medicine, Keimyung University, 1095 Dalgubeoldaero, Dalseo-Gu, Daegu 42601, KoreaNiclosamide 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.http://www.mdpi.com/1420-3049/23/9/2264niclosamideTRAILDR5c-FLIPapoptosis |
| spellingShingle | Jeong Mi Yun Seon Min Woo Seung Un Seo Kyoung-Jin Min Dong Eun Kim Taeg Kyu Kwon 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 niclosamide TRAIL DR5 c-FLIP apoptosis |
| title | Involvement of Up-Regulation of DR5 Expression and Down-Regulation of c-FLIP in Niclosamide-Mediated TRAIL Sensitization in Human Renal Carcinoma Caki Cells |
| title_full | Involvement of Up-Regulation of DR5 Expression and Down-Regulation of c-FLIP in Niclosamide-Mediated TRAIL Sensitization in Human Renal Carcinoma Caki Cells |
| title_fullStr | Involvement of Up-Regulation of DR5 Expression and Down-Regulation of c-FLIP in Niclosamide-Mediated TRAIL Sensitization in Human Renal Carcinoma Caki Cells |
| title_full_unstemmed | Involvement of Up-Regulation of DR5 Expression and Down-Regulation of c-FLIP in Niclosamide-Mediated TRAIL Sensitization in Human Renal Carcinoma Caki Cells |
| title_short | Involvement of Up-Regulation of DR5 Expression and Down-Regulation of c-FLIP in Niclosamide-Mediated TRAIL Sensitization in Human Renal Carcinoma Caki Cells |
| title_sort | involvement of up regulation of dr5 expression and down regulation of c flip in niclosamide mediated trail sensitization in human renal carcinoma caki cells |
| topic | niclosamide TRAIL DR5 c-FLIP apoptosis |
| url | http://www.mdpi.com/1420-3049/23/9/2264 |
| work_keys_str_mv | AT jeongmiyun involvementofupregulationofdr5expressionanddownregulationofcflipinniclosamidemediatedtrailsensitizationinhumanrenalcarcinomacakicells AT seonminwoo involvementofupregulationofdr5expressionanddownregulationofcflipinniclosamidemediatedtrailsensitizationinhumanrenalcarcinomacakicells AT seungunseo involvementofupregulationofdr5expressionanddownregulationofcflipinniclosamidemediatedtrailsensitizationinhumanrenalcarcinomacakicells AT kyoungjinmin involvementofupregulationofdr5expressionanddownregulationofcflipinniclosamidemediatedtrailsensitizationinhumanrenalcarcinomacakicells AT dongeunkim involvementofupregulationofdr5expressionanddownregulationofcflipinniclosamidemediatedtrailsensitizationinhumanrenalcarcinomacakicells AT taegkyukwon involvementofupregulationofdr5expressionanddownregulationofcflipinniclosamidemediatedtrailsensitizationinhumanrenalcarcinomacakicells |