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Pioglitazone mediates apoptosis in Caki cells via downregulating c-FLIP((L)) expression and reducing Bcl-2 protein stability
Pioglitazone is an anti-diabetic agent used in the treatment of type 2 diabetes, which belongs to the thiazolidinediones (TZDs) group. TZDs target peroxisome proliferator-activated receptor γ (PPARγ), which functions as a transcription factor of the nuclear hormone receptor. Pioglitazone has antitum...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
D.A. Spandidos
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8387863/ https://www.ncbi.nlm.nih.gov/pubmed/34466155 http://dx.doi.org/10.3892/ol.2021.13004 |
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author | Jang, Ji Hoon Lee, Tae-Jin Sung, Eon-Gi Song, In-Hwan Kim, Joo-Young |
author_facet | Jang, Ji Hoon Lee, Tae-Jin Sung, Eon-Gi Song, In-Hwan Kim, Joo-Young |
author_sort | Jang, Ji Hoon |
collection | PubMed |
description | Pioglitazone is an anti-diabetic agent used in the treatment of type 2 diabetes, which belongs to the thiazolidinediones (TZDs) group. TZDs target peroxisome proliferator-activated receptor γ (PPARγ), which functions as a transcription factor of the nuclear hormone receptor. Pioglitazone has antitumor effects in several cancer types and could be a tool for drug therapy in various cancer treatments. Nevertheless, the molecular basis for pioglitazone-induced anticancer effects in renal cancer (RC) has not yet been elucidated. Thus, the aim of the present study was to investigate the detailed signaling pathway underlying pioglitazone-induced apoptosis in Caki cells derived from human clear cell renal cell carcinoma. As a result, it was demonstrated by flow cytometry analysis and Annexin V-propidium iodide staining that pioglitazone treatment induced apoptotic cell death in a dose-dependent manner in Caki cells. The protein expression levels of cellular FLICE (FADD-like IL-1β-converting enzyme)-inhibitory protein (c-FLIP)((L)) and Bcl-2, which were determined by western blotting, decreased after pioglitazone treatment in Caki cells. Flow cytometry and western blot analyses demonstrated that pioglitazone-mediated apoptosis was blocked following pretreatment with the pan-caspase inhibitor, z-VAD-fmk, indicating that pioglitazone-induced apoptosis was mediated via a caspase-dependent signaling pathway. However, the reactive oxygen species (ROS) scavenger, N-acetylcysteine (NAC), did not affect pioglitazone-mediated apoptosis and degradation of c-FLIP((L)) and Bcl-2 protein. Of note, it was found by western blot analysis that Bcl-2 protein expression was downregulated by the decreased protein stability of Bcl-2 in pioglitazone-treated Caki cells. In conclusion, these findings indicated that pioglitazone-induced apoptosis is regulated through caspase-mediated degradation of FLIP((L)) and reduction of Bcl-2 protein stability, suggesting that pioglitazone is a feasible apoptotic agent that could be used in the treatment of human RC. |
format | Online Article Text |
id | pubmed-8387863 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | D.A. Spandidos |
record_format | MEDLINE/PubMed |
spelling | pubmed-83878632021-08-30 Pioglitazone mediates apoptosis in Caki cells via downregulating c-FLIP((L)) expression and reducing Bcl-2 protein stability Jang, Ji Hoon Lee, Tae-Jin Sung, Eon-Gi Song, In-Hwan Kim, Joo-Young Oncol Lett Articles Pioglitazone is an anti-diabetic agent used in the treatment of type 2 diabetes, which belongs to the thiazolidinediones (TZDs) group. TZDs target peroxisome proliferator-activated receptor γ (PPARγ), which functions as a transcription factor of the nuclear hormone receptor. Pioglitazone has antitumor effects in several cancer types and could be a tool for drug therapy in various cancer treatments. Nevertheless, the molecular basis for pioglitazone-induced anticancer effects in renal cancer (RC) has not yet been elucidated. Thus, the aim of the present study was to investigate the detailed signaling pathway underlying pioglitazone-induced apoptosis in Caki cells derived from human clear cell renal cell carcinoma. As a result, it was demonstrated by flow cytometry analysis and Annexin V-propidium iodide staining that pioglitazone treatment induced apoptotic cell death in a dose-dependent manner in Caki cells. The protein expression levels of cellular FLICE (FADD-like IL-1β-converting enzyme)-inhibitory protein (c-FLIP)((L)) and Bcl-2, which were determined by western blotting, decreased after pioglitazone treatment in Caki cells. Flow cytometry and western blot analyses demonstrated that pioglitazone-mediated apoptosis was blocked following pretreatment with the pan-caspase inhibitor, z-VAD-fmk, indicating that pioglitazone-induced apoptosis was mediated via a caspase-dependent signaling pathway. However, the reactive oxygen species (ROS) scavenger, N-acetylcysteine (NAC), did not affect pioglitazone-mediated apoptosis and degradation of c-FLIP((L)) and Bcl-2 protein. Of note, it was found by western blot analysis that Bcl-2 protein expression was downregulated by the decreased protein stability of Bcl-2 in pioglitazone-treated Caki cells. In conclusion, these findings indicated that pioglitazone-induced apoptosis is regulated through caspase-mediated degradation of FLIP((L)) and reduction of Bcl-2 protein stability, suggesting that pioglitazone is a feasible apoptotic agent that could be used in the treatment of human RC. D.A. Spandidos 2021-10 2021-08-20 /pmc/articles/PMC8387863/ /pubmed/34466155 http://dx.doi.org/10.3892/ol.2021.13004 Text en Copyright: © Jang et al. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. |
spellingShingle | Articles Jang, Ji Hoon Lee, Tae-Jin Sung, Eon-Gi Song, In-Hwan Kim, Joo-Young Pioglitazone mediates apoptosis in Caki cells via downregulating c-FLIP((L)) expression and reducing Bcl-2 protein stability |
title | Pioglitazone mediates apoptosis in Caki cells via downregulating c-FLIP((L)) expression and reducing Bcl-2 protein stability |
title_full | Pioglitazone mediates apoptosis in Caki cells via downregulating c-FLIP((L)) expression and reducing Bcl-2 protein stability |
title_fullStr | Pioglitazone mediates apoptosis in Caki cells via downregulating c-FLIP((L)) expression and reducing Bcl-2 protein stability |
title_full_unstemmed | Pioglitazone mediates apoptosis in Caki cells via downregulating c-FLIP((L)) expression and reducing Bcl-2 protein stability |
title_short | Pioglitazone mediates apoptosis in Caki cells via downregulating c-FLIP((L)) expression and reducing Bcl-2 protein stability |
title_sort | pioglitazone mediates apoptosis in caki cells via downregulating c-flip((l)) expression and reducing bcl-2 protein stability |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8387863/ https://www.ncbi.nlm.nih.gov/pubmed/34466155 http://dx.doi.org/10.3892/ol.2021.13004 |
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