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other·oncology, gastroenterology, preclinical research, biomedical research·PMC10001020

A Novel Phenazine Analog, CPUL1, Suppresses Autophagic Flux and Proliferation in Hepatocellular Carcinoma: Insight from Integrated Transcriptomic and Metabolomic Analysis

Cancers · 12 authors, 5 centres

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TL;DR

This preclinical study used human hepatocellular carcinoma (HCC) cell lines and a xenograft mouse model to investigate the antitumor effects of the phenazine analog CPUL1. The main finding is that CPUL1 inhibits HCC cell proliferation and induces metabolic dysfunction, which is linked to the suppression of autophagic flux via lysosomal dysfunction.

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BACKGROUND

Hepatocellular carcinoma (HCC) is a lethal liver cancer with limited effective therapies. CPUL1, a synthetic phenazine derivative, has shown antitumor potential, but its mechanisms are unclear. This study aimed to elucidate CPUL1's anti-HCC effects using integrated omics. Methods: The study employed human HCC cell lines (BEL-7402, HepG2, HUH-7) in vitro and a BEL-7402 xenograft nude mouse model in vivo. Cell viability, colony formation, and tumor growth were assessed. Integrated transcriptomics (RNA-Seq) and untargeted metabolomics (LC-QTOF/MS) were performed on BEL-7402 cells treated with CPUL1 (8 μM) for 6 h and 48 h. Multi-omics analysis revealed a time-dependent deterioration in metabolic function, characterized by depletion of glycolysis intermediates, nucleotides, and amino acids, alongside accumulation of certain lipids. This metabolic stress was linked to the suppression of autophagic flux. CPUL1 treatment increased LC3-II and p62 levels, indicating autophagosome accumulation, and impaired lysosomal function (reduced LAMP1/2, RAb7 expression, and lysosomal alkalization), thereby blocking autophagosome-lysosome fusion. Limitations: The study is preclinical, using cell lines and immunocompromised mice, so findings may not directly translate to human HCC. The mechanisms are complex and require further validation. Implications: CPUL1 demonstrates promising anti-HCC activity by inducing metabolic dysfunction and blocking autophagy, suggesting it could be a candidate for further development as a therapeutic agent, though human clinical trials are needed.

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other

SPECIALTY

oncology

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ORIGINAL PAPER

PMC10001020

A Novel Phenazine Analog, CPUL1, Suppresses Autophagic Flux and Proliferation in Hepatocellular Carcinoma: Insight from Integrated Transcriptomic and Metabolomic Analysis

Cancers

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ABSTRACT

Abstract 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. Keywords: CPUL1, hepatocellular carcinoma, transcriptomics, metabolomics, autophagy

CITATION EXPORT

Jiaqin Chen, Dong Feng, Yuanyuan Lu et al.. A Novel Phenazine Analog, CPUL1, Suppresses Autophagic Flux and Proliferation in Hepatocellular Carcinoma: Insight from Integrated Transcriptomic and Metabolomic Analysis. Cancers. (2023). https://doi.org/10.3390/cancers15051607

AUTHORS

12 · 5 CENTRES

Jiaqin Chen, Dong Feng, Yuanyuan Lu, Yanjun Zhang, Hanxiang Jiang, Man Yuan, Yifan Xu, Jianjun Zou, Yubing Zhu, Jingjing Zhang, Chun Ge, Ying Wang

1School of Life Science and Technology, China Pharmaceutical University, Nanjing 211198, China
2Nanjing Southern Pharmaceutical Technology Co., Ltd., Nanjing 211100, China
3Department of Clinical Pharmacy, School of Basic Medicine & Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, China
4Department of Pharmacy, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, China
5Department of Clinical Pharmacology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, China