Cargando…
Calyxin Y sensitizes cisplatin-sensitive and resistant hepatocellular carcinoma cells to cisplatin through apoptotic and autophagic cell death via SCF βTrCP-mediated eEF2K degradation
The down-regulation of eukaryotic elongation factor-2 kinase (eEF2K) is associated with an enhancement in the sensitivity of malignant cells to chemotherapeutic agents. In this study, we found that the silencing of eEF2K enhanced cisplatin (CDDP)-induced cytotoxicity in CDDP-sensitive (HepG2) and re...
Autores principales: | , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2017
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5642580/ https://www.ncbi.nlm.nih.gov/pubmed/29050305 http://dx.doi.org/10.18632/oncotarget.19883 |
_version_ | 1783271395713613824 |
---|---|
author | Zhang, Chao Lei, Jian-Li Zhang, Hao Xia, Yuan-Zheng Yu, Pei Yang, Lei Kong, Ling-Yi |
author_facet | Zhang, Chao Lei, Jian-Li Zhang, Hao Xia, Yuan-Zheng Yu, Pei Yang, Lei Kong, Ling-Yi |
author_sort | Zhang, Chao |
collection | PubMed |
description | The down-regulation of eukaryotic elongation factor-2 kinase (eEF2K) is associated with an enhancement in the sensitivity of malignant cells to chemotherapeutic agents. In this study, we found that the silencing of eEF2K enhanced cisplatin (CDDP)-induced cytotoxicity in CDDP-sensitive (HepG2) and resistant (HepG2/CDDP) cells. Calyxin Y, a unique chalcone diarylheptanoid adduct, down-regulated eEF2K by promoting Skp1-Cul1-F-box protein (SCF) β-transducin repeat-containing protein (βTrCP)-mediated protein degradation and synergistically enhanced the cytotoxicity of CDDP. Subsequently, we identified a potential mechanism of this cooperative interaction by showing that the combination of calyxin Y and CDDP enhanced apoptotic cell death via mitochondrial dysfunction. In addition, the combination induced autophagy, which contributed to the synergistic cytotoxic effect. Further research revealed that calyxin Y synergistically sensitized HepG2 and HepG2/CDDP cells to CDDP through enhanced apoptotic and autophagic cell death via the SCF βTrCP-eEF2K pathway. Finally, in vivo studies demonstrated that calyxin Y could enhance the response of HepG2/CDDP cells to CDDP in xenograft models with low systemic toxicity. Thus, the combination of calyxin Y and CDDP might represent an attractive therapeutic strategy for the treatment of chemotherapy-sensitive and resistant hepatocellular carcinoma cells. |
format | Online Article Text |
id | pubmed-5642580 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-56425802017-10-18 Calyxin Y sensitizes cisplatin-sensitive and resistant hepatocellular carcinoma cells to cisplatin through apoptotic and autophagic cell death via SCF βTrCP-mediated eEF2K degradation Zhang, Chao Lei, Jian-Li Zhang, Hao Xia, Yuan-Zheng Yu, Pei Yang, Lei Kong, Ling-Yi Oncotarget Research Paper The down-regulation of eukaryotic elongation factor-2 kinase (eEF2K) is associated with an enhancement in the sensitivity of malignant cells to chemotherapeutic agents. In this study, we found that the silencing of eEF2K enhanced cisplatin (CDDP)-induced cytotoxicity in CDDP-sensitive (HepG2) and resistant (HepG2/CDDP) cells. Calyxin Y, a unique chalcone diarylheptanoid adduct, down-regulated eEF2K by promoting Skp1-Cul1-F-box protein (SCF) β-transducin repeat-containing protein (βTrCP)-mediated protein degradation and synergistically enhanced the cytotoxicity of CDDP. Subsequently, we identified a potential mechanism of this cooperative interaction by showing that the combination of calyxin Y and CDDP enhanced apoptotic cell death via mitochondrial dysfunction. In addition, the combination induced autophagy, which contributed to the synergistic cytotoxic effect. Further research revealed that calyxin Y synergistically sensitized HepG2 and HepG2/CDDP cells to CDDP through enhanced apoptotic and autophagic cell death via the SCF βTrCP-eEF2K pathway. Finally, in vivo studies demonstrated that calyxin Y could enhance the response of HepG2/CDDP cells to CDDP in xenograft models with low systemic toxicity. Thus, the combination of calyxin Y and CDDP might represent an attractive therapeutic strategy for the treatment of chemotherapy-sensitive and resistant hepatocellular carcinoma cells. Impact Journals LLC 2017-08-03 /pmc/articles/PMC5642580/ /pubmed/29050305 http://dx.doi.org/10.18632/oncotarget.19883 Text en Copyright: © 2017 Zhang et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/) 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Paper Zhang, Chao Lei, Jian-Li Zhang, Hao Xia, Yuan-Zheng Yu, Pei Yang, Lei Kong, Ling-Yi Calyxin Y sensitizes cisplatin-sensitive and resistant hepatocellular carcinoma cells to cisplatin through apoptotic and autophagic cell death via SCF βTrCP-mediated eEF2K degradation |
title | Calyxin Y sensitizes cisplatin-sensitive and resistant hepatocellular carcinoma cells to cisplatin through apoptotic and autophagic cell death via SCF βTrCP-mediated eEF2K degradation |
title_full | Calyxin Y sensitizes cisplatin-sensitive and resistant hepatocellular carcinoma cells to cisplatin through apoptotic and autophagic cell death via SCF βTrCP-mediated eEF2K degradation |
title_fullStr | Calyxin Y sensitizes cisplatin-sensitive and resistant hepatocellular carcinoma cells to cisplatin through apoptotic and autophagic cell death via SCF βTrCP-mediated eEF2K degradation |
title_full_unstemmed | Calyxin Y sensitizes cisplatin-sensitive and resistant hepatocellular carcinoma cells to cisplatin through apoptotic and autophagic cell death via SCF βTrCP-mediated eEF2K degradation |
title_short | Calyxin Y sensitizes cisplatin-sensitive and resistant hepatocellular carcinoma cells to cisplatin through apoptotic and autophagic cell death via SCF βTrCP-mediated eEF2K degradation |
title_sort | calyxin y sensitizes cisplatin-sensitive and resistant hepatocellular carcinoma cells to cisplatin through apoptotic and autophagic cell death via scf βtrcp-mediated eef2k degradation |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5642580/ https://www.ncbi.nlm.nih.gov/pubmed/29050305 http://dx.doi.org/10.18632/oncotarget.19883 |
work_keys_str_mv | AT zhangchao calyxinysensitizescisplatinsensitiveandresistanthepatocellularcarcinomacellstocisplatinthroughapoptoticandautophagiccelldeathviascfbtrcpmediatedeef2kdegradation AT leijianli calyxinysensitizescisplatinsensitiveandresistanthepatocellularcarcinomacellstocisplatinthroughapoptoticandautophagiccelldeathviascfbtrcpmediatedeef2kdegradation AT zhanghao calyxinysensitizescisplatinsensitiveandresistanthepatocellularcarcinomacellstocisplatinthroughapoptoticandautophagiccelldeathviascfbtrcpmediatedeef2kdegradation AT xiayuanzheng calyxinysensitizescisplatinsensitiveandresistanthepatocellularcarcinomacellstocisplatinthroughapoptoticandautophagiccelldeathviascfbtrcpmediatedeef2kdegradation AT yupei calyxinysensitizescisplatinsensitiveandresistanthepatocellularcarcinomacellstocisplatinthroughapoptoticandautophagiccelldeathviascfbtrcpmediatedeef2kdegradation AT yanglei calyxinysensitizescisplatinsensitiveandresistanthepatocellularcarcinomacellstocisplatinthroughapoptoticandautophagiccelldeathviascfbtrcpmediatedeef2kdegradation AT konglingyi calyxinysensitizescisplatinsensitiveandresistanthepatocellularcarcinomacellstocisplatinthroughapoptoticandautophagiccelldeathviascfbtrcpmediatedeef2kdegradation |