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Natural Cyclopeptide RA-XII, a New Autophagy Inhibitor, Suppresses Protective Autophagy for Enhancing Apoptosis through AMPK/mTOR/P70S6K Pathways in HepG2 Cells
Liver cancer is a progressive, irreversible and aggressive malignant disease, which has no effective chemotherapeutic drugs. RA-XII, a natural cyclopeptide isolated from the traditional Chinese medicine Rubia yunnanensis, exerts anti-cancer and anti-inflammatory activities. This work aimed to invest...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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MDPI
2017
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6150396/ https://www.ncbi.nlm.nih.gov/pubmed/29137114 http://dx.doi.org/10.3390/molecules22111934 |
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author | Song, Lihua Wang, Zhe Wang, Yurong Guo, Di Yang, Jianhong Chen, Lijuan Tan, Ninghua |
author_facet | Song, Lihua Wang, Zhe Wang, Yurong Guo, Di Yang, Jianhong Chen, Lijuan Tan, Ninghua |
author_sort | Song, Lihua |
collection | PubMed |
description | Liver cancer is a progressive, irreversible and aggressive malignant disease, which has no effective chemotherapeutic drugs. RA-XII, a natural cyclopeptide isolated from the traditional Chinese medicine Rubia yunnanensis, exerts anti-cancer and anti-inflammatory activities. This work aimed to investigate the effects of RA-XII on a hepatic tumor and its underlying mechanisms in human hepatoma HepG2 cells. The results showed that RA-XII effectively inhibited the proliferation of HepG2 cells. Consistently, RA-XII significantly induced apoptosis in HepG2 cells by decreasing the expression of caspase 3, 8, 9, and promoting the Cleavage of PARP. Moreover, RA-XII-induced apoptosis was attenuated in the presence of apoptosis inhibitor N-Benzyloxycarbonyl-Val-Ala-Asp (O-Me) fluoromethyl keton, suggesting that RA-XII induced apoptosis-cell-death in HepG2 cells. Furthermore, autophagy-related proteins and mRNA levels were dramatically reduced after RA-XII treatment. Meanwhile, we observed that autophagy inhibitor chloroquine could enhance apoptosis in RA-XII-treated HepG2 cells, indicating that autophagy played a protective role in HepG2 cells and RA-XII might inhibit protective autophagy. Further analysis showed that RA-XII inhibited AMPK phosphorylation and led to the mTOR/P70S6K pathway activation, suggesting that RA-XII inhibited autophagy through AMPK/mTOR/P70S6K pathways. This study demonstrated that RA-XII promoted apoptosis and inhibited protective autophagy through AMPK/mTOR/P70S6K pathways in HepG2 cells. In conclusion, these findings suggest that RA-XII might potentially be a candidate as an autophagy inhibitor agent for further therapy of liver cancer. |
format | Online Article Text |
id | pubmed-6150396 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-61503962018-11-13 Natural Cyclopeptide RA-XII, a New Autophagy Inhibitor, Suppresses Protective Autophagy for Enhancing Apoptosis through AMPK/mTOR/P70S6K Pathways in HepG2 Cells Song, Lihua Wang, Zhe Wang, Yurong Guo, Di Yang, Jianhong Chen, Lijuan Tan, Ninghua Molecules Article Liver cancer is a progressive, irreversible and aggressive malignant disease, which has no effective chemotherapeutic drugs. RA-XII, a natural cyclopeptide isolated from the traditional Chinese medicine Rubia yunnanensis, exerts anti-cancer and anti-inflammatory activities. This work aimed to investigate the effects of RA-XII on a hepatic tumor and its underlying mechanisms in human hepatoma HepG2 cells. The results showed that RA-XII effectively inhibited the proliferation of HepG2 cells. Consistently, RA-XII significantly induced apoptosis in HepG2 cells by decreasing the expression of caspase 3, 8, 9, and promoting the Cleavage of PARP. Moreover, RA-XII-induced apoptosis was attenuated in the presence of apoptosis inhibitor N-Benzyloxycarbonyl-Val-Ala-Asp (O-Me) fluoromethyl keton, suggesting that RA-XII induced apoptosis-cell-death in HepG2 cells. Furthermore, autophagy-related proteins and mRNA levels were dramatically reduced after RA-XII treatment. Meanwhile, we observed that autophagy inhibitor chloroquine could enhance apoptosis in RA-XII-treated HepG2 cells, indicating that autophagy played a protective role in HepG2 cells and RA-XII might inhibit protective autophagy. Further analysis showed that RA-XII inhibited AMPK phosphorylation and led to the mTOR/P70S6K pathway activation, suggesting that RA-XII inhibited autophagy through AMPK/mTOR/P70S6K pathways. This study demonstrated that RA-XII promoted apoptosis and inhibited protective autophagy through AMPK/mTOR/P70S6K pathways in HepG2 cells. In conclusion, these findings suggest that RA-XII might potentially be a candidate as an autophagy inhibitor agent for further therapy of liver cancer. MDPI 2017-11-11 /pmc/articles/PMC6150396/ /pubmed/29137114 http://dx.doi.org/10.3390/molecules22111934 Text en © 2017 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Song, Lihua Wang, Zhe Wang, Yurong Guo, Di Yang, Jianhong Chen, Lijuan Tan, Ninghua Natural Cyclopeptide RA-XII, a New Autophagy Inhibitor, Suppresses Protective Autophagy for Enhancing Apoptosis through AMPK/mTOR/P70S6K Pathways in HepG2 Cells |
title | Natural Cyclopeptide RA-XII, a New Autophagy Inhibitor, Suppresses Protective Autophagy for Enhancing Apoptosis through AMPK/mTOR/P70S6K Pathways in HepG2 Cells |
title_full | Natural Cyclopeptide RA-XII, a New Autophagy Inhibitor, Suppresses Protective Autophagy for Enhancing Apoptosis through AMPK/mTOR/P70S6K Pathways in HepG2 Cells |
title_fullStr | Natural Cyclopeptide RA-XII, a New Autophagy Inhibitor, Suppresses Protective Autophagy for Enhancing Apoptosis through AMPK/mTOR/P70S6K Pathways in HepG2 Cells |
title_full_unstemmed | Natural Cyclopeptide RA-XII, a New Autophagy Inhibitor, Suppresses Protective Autophagy for Enhancing Apoptosis through AMPK/mTOR/P70S6K Pathways in HepG2 Cells |
title_short | Natural Cyclopeptide RA-XII, a New Autophagy Inhibitor, Suppresses Protective Autophagy for Enhancing Apoptosis through AMPK/mTOR/P70S6K Pathways in HepG2 Cells |
title_sort | natural cyclopeptide ra-xii, a new autophagy inhibitor, suppresses protective autophagy for enhancing apoptosis through ampk/mtor/p70s6k pathways in hepg2 cells |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6150396/ https://www.ncbi.nlm.nih.gov/pubmed/29137114 http://dx.doi.org/10.3390/molecules22111934 |
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