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A Novel Phenazine Analog, CPUL1, Suppresses Autophagic Flux and Proliferation in Hepatocellular Carcinoma: Insight from Integrated Transcriptomic and Metabolomic Analysis
SIMPLE SUMMARY: CPUL1 exhibits antitumor properties against hepatocellular carcinoma (HCC), although the underlying mechanisms remain unclear. Our study provides a comprehensive overview of the properties and molecular mechanisms of CPUL1 anti-HCC using transcriptomics and metabolomics and highlight...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10001020/ https://www.ncbi.nlm.nih.gov/pubmed/36900398 http://dx.doi.org/10.3390/cancers15051607 |
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author | Chen, Jiaqin Feng, Dong Lu, Yuanyuan Zhang, Yanjun Jiang, Hanxiang Yuan, Man Xu, Yifan Zou, Jianjun Zhu, Yubing Zhang, Jingjing Ge, Chun Wang, Ying |
author_facet | Chen, Jiaqin Feng, Dong Lu, Yuanyuan Zhang, Yanjun Jiang, Hanxiang Yuan, Man Xu, Yifan Zou, Jianjun Zhu, Yubing Zhang, Jingjing Ge, Chun Wang, Ying |
author_sort | Chen, Jiaqin |
collection | PubMed |
description | SIMPLE SUMMARY: CPUL1 exhibits antitumor properties against hepatocellular carcinoma (HCC), although the underlying mechanisms remain unclear. Our study provides a comprehensive overview of the properties and molecular mechanisms of CPUL1 anti-HCC using transcriptomics and metabolomics and highlights the significance of progressive metabolic failure. This may be partially attributable to autophagy blockage, which is presumed to contribute to nutrient deprivation and increased cell susceptibility to stress. Therefore, the attractive properties of CPUL1 may endow this compound with the potential of becoming a promising anti-HCC agent. ABSTRACT: Background: CPUL1, a phenazine analog, has demonstrated potent antitumor properties against hepatocellular carcinoma (HCC) and indicates a promising prospect in pharmaceutical development. However, the underlying mechanisms remain largely obscure. Methods: Multiple HCC cell lines were used to investigate the in vitro effects of CPUL1. The antineoplastic properties of CPUL1 were assessed in vivo by establishing a xenograft nude mice model. After that, metabolomics, transcriptomics, and bioinformatics were integrated to elucidate the mechanisms underlying the therapeutic efficacy of CPUL1, highlighting an unanticipated involvement of autophagy dysregulation. Results: CPUL1 suppressed HCC cell proliferation in vitro and in vivo, thereby endorsing the potential as a leading agent for HCC therapy. Integrative omics characterized a deteriorating scenario of metabolic debilitation with CPUL1, presenting an issue in the autophagy contribution of autophagy. Subsequent observations indicated that CPUL1 treatment could impede autophagic flow by suppressing autophagosome degradation rather than its formation, which supposedly exacerbated cellular damage triggered by metabolic impairment. Moreover, the observed late autophagosome degradation may be attributed to lysosome dysfunction, which is essential for the final stage of autophagy and cargo disposal. Conclusions: Our study comprehensively profiled the anti-hepatoma characteristics and molecular mechanisms of CPUL1, highlighting the implications of progressive metabolic failure. This could partially be ascribed to autophagy blockage, which supposedly conveyed nutritional deprivation and intensified cellular vulnerability to stress. |
format | Online Article Text |
id | pubmed-10001020 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-100010202023-03-11 A Novel Phenazine Analog, CPUL1, Suppresses Autophagic Flux and Proliferation in Hepatocellular Carcinoma: Insight from Integrated Transcriptomic and Metabolomic Analysis Chen, Jiaqin Feng, Dong Lu, Yuanyuan Zhang, Yanjun Jiang, Hanxiang Yuan, Man Xu, Yifan Zou, Jianjun Zhu, Yubing Zhang, Jingjing Ge, Chun Wang, Ying Cancers (Basel) Article SIMPLE SUMMARY: CPUL1 exhibits antitumor properties against hepatocellular carcinoma (HCC), although the underlying mechanisms remain unclear. Our study provides a comprehensive overview of the properties and molecular mechanisms of CPUL1 anti-HCC using transcriptomics and metabolomics and highlights the significance of progressive metabolic failure. This may be partially attributable to autophagy blockage, which is presumed to contribute to nutrient deprivation and increased cell susceptibility to stress. Therefore, the attractive properties of CPUL1 may endow this compound with the potential of becoming a promising anti-HCC agent. ABSTRACT: Background: CPUL1, a phenazine analog, has demonstrated potent antitumor properties against hepatocellular carcinoma (HCC) and indicates a promising prospect in pharmaceutical development. However, the underlying mechanisms remain largely obscure. Methods: Multiple HCC cell lines were used to investigate the in vitro effects of CPUL1. The antineoplastic properties of CPUL1 were assessed in vivo by establishing a xenograft nude mice model. After that, metabolomics, transcriptomics, and bioinformatics were integrated to elucidate the mechanisms underlying the therapeutic efficacy of CPUL1, highlighting an unanticipated involvement of autophagy dysregulation. Results: CPUL1 suppressed HCC cell proliferation in vitro and in vivo, thereby endorsing the potential as a leading agent for HCC therapy. Integrative omics characterized a deteriorating scenario of metabolic debilitation with CPUL1, presenting an issue in the autophagy contribution of autophagy. Subsequent observations indicated that CPUL1 treatment could impede autophagic flow by suppressing autophagosome degradation rather than its formation, which supposedly exacerbated cellular damage triggered by metabolic impairment. Moreover, the observed late autophagosome degradation may be attributed to lysosome dysfunction, which is essential for the final stage of autophagy and cargo disposal. Conclusions: Our study comprehensively profiled the anti-hepatoma characteristics and molecular mechanisms of CPUL1, highlighting the implications of progressive metabolic failure. This could partially be ascribed to autophagy blockage, which supposedly conveyed nutritional deprivation and intensified cellular vulnerability to stress. MDPI 2023-03-05 /pmc/articles/PMC10001020/ /pubmed/36900398 http://dx.doi.org/10.3390/cancers15051607 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/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 (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Chen, Jiaqin Feng, Dong Lu, Yuanyuan Zhang, Yanjun Jiang, Hanxiang Yuan, Man Xu, Yifan Zou, Jianjun Zhu, Yubing Zhang, Jingjing Ge, Chun Wang, Ying A Novel Phenazine Analog, CPUL1, Suppresses Autophagic Flux and Proliferation in Hepatocellular Carcinoma: Insight from Integrated Transcriptomic and Metabolomic Analysis |
title | A Novel Phenazine Analog, CPUL1, Suppresses Autophagic Flux and Proliferation in Hepatocellular Carcinoma: Insight from Integrated Transcriptomic and Metabolomic Analysis |
title_full | A Novel Phenazine Analog, CPUL1, Suppresses Autophagic Flux and Proliferation in Hepatocellular Carcinoma: Insight from Integrated Transcriptomic and Metabolomic Analysis |
title_fullStr | A Novel Phenazine Analog, CPUL1, Suppresses Autophagic Flux and Proliferation in Hepatocellular Carcinoma: Insight from Integrated Transcriptomic and Metabolomic Analysis |
title_full_unstemmed | A Novel Phenazine Analog, CPUL1, Suppresses Autophagic Flux and Proliferation in Hepatocellular Carcinoma: Insight from Integrated Transcriptomic and Metabolomic Analysis |
title_short | A Novel Phenazine Analog, CPUL1, Suppresses Autophagic Flux and Proliferation in Hepatocellular Carcinoma: Insight from Integrated Transcriptomic and Metabolomic Analysis |
title_sort | novel phenazine analog, cpul1, suppresses autophagic flux and proliferation in hepatocellular carcinoma: insight from integrated transcriptomic and metabolomic analysis |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10001020/ https://www.ncbi.nlm.nih.gov/pubmed/36900398 http://dx.doi.org/10.3390/cancers15051607 |
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