Cargando…
The combination of lonafarnib and sorafenib induces cyclin D1 degradation via ATG3-mediated autophagic flux in hepatocellular carcinoma cells
Combination treatment is a promising strategy to improve prognosis of hepatocellular carcinoma (HCC). Sorafenib is a traditional first-line agent approved for the treatment of advanced HCC, though with limited efficacy. Previously, we reported that lonafarnib, an orally bioavailable non-peptide inhi...
Autores principales: | , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals
2019
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6710066/ https://www.ncbi.nlm.nih.gov/pubmed/31409760 http://dx.doi.org/10.18632/aging.102165 |
_version_ | 1783446288880107520 |
---|---|
author | Wang, Jialiang Wei, Huan Huang, Yanlin Chen, Dongmei Zeng, Guofen Lian, Yifan Huang, Yuehua |
author_facet | Wang, Jialiang Wei, Huan Huang, Yanlin Chen, Dongmei Zeng, Guofen Lian, Yifan Huang, Yuehua |
author_sort | Wang, Jialiang |
collection | PubMed |
description | Combination treatment is a promising strategy to improve prognosis of hepatocellular carcinoma (HCC). Sorafenib is a traditional first-line agent approved for the treatment of advanced HCC, though with limited efficacy. Previously, we reported that lonafarnib, an orally bioavailable non-peptide inhibitor targeting farnesyltransferase, synergizes with sorafenib against the growth of HCC cells. In the present study, we aim to clarify the underlying mechanism of this combination strategy. Initially, using in vitro HCC cell model, we confirmed that synergistic treatment of lonafarnib and sorafenib suppressed cell viability and colony formation, and induced cell death. We then found conversion of LC3-I to LC3-II via combination the treatment and observed formation of autophagosomes by electron microscopy. Knockdown of ATG3 inhibited the autophagic flux induced by the combination treatment. Furthermore, we demonstrated that drug-eliciting autophagy selectively promoted the degradation of cyclin D1 in a lysosome-dependent manner and subsequently inhibited DNA synthesis through downregulating the phosphorylation of Rb protein. In conclusion, our results provide a deeper insight into the mechanism for the combination treatment of lonafarnib and sorafenib in HCC therapy. |
format | Online Article Text |
id | pubmed-6710066 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Impact Journals |
record_format | MEDLINE/PubMed |
spelling | pubmed-67100662019-09-05 The combination of lonafarnib and sorafenib induces cyclin D1 degradation via ATG3-mediated autophagic flux in hepatocellular carcinoma cells Wang, Jialiang Wei, Huan Huang, Yanlin Chen, Dongmei Zeng, Guofen Lian, Yifan Huang, Yuehua Aging (Albany NY) Research Paper Combination treatment is a promising strategy to improve prognosis of hepatocellular carcinoma (HCC). Sorafenib is a traditional first-line agent approved for the treatment of advanced HCC, though with limited efficacy. Previously, we reported that lonafarnib, an orally bioavailable non-peptide inhibitor targeting farnesyltransferase, synergizes with sorafenib against the growth of HCC cells. In the present study, we aim to clarify the underlying mechanism of this combination strategy. Initially, using in vitro HCC cell model, we confirmed that synergistic treatment of lonafarnib and sorafenib suppressed cell viability and colony formation, and induced cell death. We then found conversion of LC3-I to LC3-II via combination the treatment and observed formation of autophagosomes by electron microscopy. Knockdown of ATG3 inhibited the autophagic flux induced by the combination treatment. Furthermore, we demonstrated that drug-eliciting autophagy selectively promoted the degradation of cyclin D1 in a lysosome-dependent manner and subsequently inhibited DNA synthesis through downregulating the phosphorylation of Rb protein. In conclusion, our results provide a deeper insight into the mechanism for the combination treatment of lonafarnib and sorafenib in HCC therapy. Impact Journals 2019-08-13 /pmc/articles/PMC6710066/ /pubmed/31409760 http://dx.doi.org/10.18632/aging.102165 Text en Copyright © 2019 Wang et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution (CC BY) 3.0 License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Paper Wang, Jialiang Wei, Huan Huang, Yanlin Chen, Dongmei Zeng, Guofen Lian, Yifan Huang, Yuehua The combination of lonafarnib and sorafenib induces cyclin D1 degradation via ATG3-mediated autophagic flux in hepatocellular carcinoma cells |
title | The combination of lonafarnib and sorafenib induces cyclin D1 degradation via ATG3-mediated autophagic flux in hepatocellular carcinoma cells |
title_full | The combination of lonafarnib and sorafenib induces cyclin D1 degradation via ATG3-mediated autophagic flux in hepatocellular carcinoma cells |
title_fullStr | The combination of lonafarnib and sorafenib induces cyclin D1 degradation via ATG3-mediated autophagic flux in hepatocellular carcinoma cells |
title_full_unstemmed | The combination of lonafarnib and sorafenib induces cyclin D1 degradation via ATG3-mediated autophagic flux in hepatocellular carcinoma cells |
title_short | The combination of lonafarnib and sorafenib induces cyclin D1 degradation via ATG3-mediated autophagic flux in hepatocellular carcinoma cells |
title_sort | combination of lonafarnib and sorafenib induces cyclin d1 degradation via atg3-mediated autophagic flux in hepatocellular carcinoma cells |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6710066/ https://www.ncbi.nlm.nih.gov/pubmed/31409760 http://dx.doi.org/10.18632/aging.102165 |
work_keys_str_mv | AT wangjialiang thecombinationoflonafarnibandsorafenibinducescyclind1degradationviaatg3mediatedautophagicfluxinhepatocellularcarcinomacells AT weihuan thecombinationoflonafarnibandsorafenibinducescyclind1degradationviaatg3mediatedautophagicfluxinhepatocellularcarcinomacells AT huangyanlin thecombinationoflonafarnibandsorafenibinducescyclind1degradationviaatg3mediatedautophagicfluxinhepatocellularcarcinomacells AT chendongmei thecombinationoflonafarnibandsorafenibinducescyclind1degradationviaatg3mediatedautophagicfluxinhepatocellularcarcinomacells AT zengguofen thecombinationoflonafarnibandsorafenibinducescyclind1degradationviaatg3mediatedautophagicfluxinhepatocellularcarcinomacells AT lianyifan thecombinationoflonafarnibandsorafenibinducescyclind1degradationviaatg3mediatedautophagicfluxinhepatocellularcarcinomacells AT huangyuehua thecombinationoflonafarnibandsorafenibinducescyclind1degradationviaatg3mediatedautophagicfluxinhepatocellularcarcinomacells AT wangjialiang combinationoflonafarnibandsorafenibinducescyclind1degradationviaatg3mediatedautophagicfluxinhepatocellularcarcinomacells AT weihuan combinationoflonafarnibandsorafenibinducescyclind1degradationviaatg3mediatedautophagicfluxinhepatocellularcarcinomacells AT huangyanlin combinationoflonafarnibandsorafenibinducescyclind1degradationviaatg3mediatedautophagicfluxinhepatocellularcarcinomacells AT chendongmei combinationoflonafarnibandsorafenibinducescyclind1degradationviaatg3mediatedautophagicfluxinhepatocellularcarcinomacells AT zengguofen combinationoflonafarnibandsorafenibinducescyclind1degradationviaatg3mediatedautophagicfluxinhepatocellularcarcinomacells AT lianyifan combinationoflonafarnibandsorafenibinducescyclind1degradationviaatg3mediatedautophagicfluxinhepatocellularcarcinomacells AT huangyuehua combinationoflonafarnibandsorafenibinducescyclind1degradationviaatg3mediatedautophagicfluxinhepatocellularcarcinomacells |