Aloe-Emodin Induces Mitochondrial Dysfunction and Pyroptosis by Activation of the Caspase-9/3/Gasdermin E Axis in HeLa Cells

Li, Tonghui; Shi, Liu-liu; Liu, Wenqiang; Hu, Xueyi; Hui, Yuanjian; Di, Maojun; Xue, Sheng‐Li; Yan, Zheng; Yao, Mengjuan; Li, Chen; Meng, Kun

doi:10.3389/fphar.2022.854526

Cited by 12 publications

(7 citation statements)

References 42 publications

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“…SRC had similar binding energy to that of its original ligand. AKT1, TP53, ESR1, SRC, and EGFR had energy <−5 kcal/Mol, demonstrating that these five core targets of AE play an important role in the treatment of HCC( Li et al, 2021 ; Liu et al, 2021 ; Li T. et al, 2022 ). The docking results were visualized through PyMOL ( Figures 6 , 7 ).…”

Section: Resultsmentioning

confidence: 99%

Exploring the mechanism of aloe-emodin in the treatment of liver cancer through network pharmacology and cell experiments

Zhu,

He,

Wang

et al. 2023

Front. Pharmacol.

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Objective: Aloe-emodin (AE) is an anthraquinone compound extracted from the rhizome of the natural plant rhubarb. Initially, it was shown that AE exerts an anti-inflammatory effect. Further studies revealed its antitumor activity against various types of cancer. However, the mechanisms underlying these properties remain unclear. Based on network pharmacology and molecular docking, this study investigated the molecular mechanism of AE in the treatment of hepatocellular carcinoma (HCC), and evaluated its therapeutic effect through in vitro experiments.Methods: CTD, Pharmmapper, SuperPred and TargetNet were the databases to obtain potential drug-related targets. DisGenet, GeneCards, OMIM and TTD were used to identify potential disease-related targets. Intersection genes for drugs and diseases were obtained through the Venn diagram. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses of intersecting genes were conducted by the website of Bioinformatics. Intersection genes were introduced into STRING to construct a protein-protein interaction network, while the Cytoscape3.9.1 software was used to visualize and analyze the core targets. AutoDock4.2.6 was utilized to achieve molecular docking between drug and core targets. In vitro experiments investigated the therapeutic effects and related mechanisms of AE.Results: 63 overlapped genes were obtained and GO analysis generated 3,646 entries by these 63 intersecting genes. KEGG analysis mainly involved apoptosis, proteoglycans in cancer, TNF signaling pathway, TP53 signaling pathway, PI3K-AKT signaling pathway, etc. AKT1, EGFR, ESR1, TP53, and SRC have been identified as core targets because the binding energies of them between aloe-emodin were less than -5 kcal/Mol.The mRNA and protein expression, prognosis, mutation status, and immune infiltration related to core targets were further revealed. The involvement of AKT1 and EGFR, as well as the key target of the PI3K-AKT signaling pathway, indicated the importance of this signaling pathway in the treatment of HCC using AE. The results of the Cell Counting Kit-8 assay and flow analysis demonstrated the therapeutic effect of AE. The downregulation of EGFR, PI3KR1, AKT1, and BCL2 in mRNA expression and PI3KR1, AKT,p-AKT in protein expression confirmed our hypothesis.Conclusion: Based on network pharmacology and molecular docking, our study initially showed that AE exerted a therapeutic effect on HCC by modulating multiple signaling pathways. Various analyses confirmed the antiproliferative activity and pro-apoptotic effect of AE on HCC through the PI3K-AKT signaling pathway. This study revealed the therapeutic mechanism of AE in the treatment of HCC through a novel approach, providing a theoretical basis for the clinical application of AE.

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Section: Resultsmentioning

confidence: 99%

Exploring the mechanism of aloe-emodin in the treatment of liver cancer through network pharmacology and cell experiments

Zhu,

He,

Wang

et al. 2023

Front. Pharmacol.

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“…Caspase-3 activity was measured as described previously [ 36 ]. Briefly, equal volumes of cell lysates were mixed and incubated with reaction buffer (1 M sodium citrate, 10 mM dithiothreitol, and 50 mM Tris-HCl, pH 7.4) containing Ac-DEVD-AFC (20 μM final) for 30 min at 37 °C.…”

Section: Methodsmentioning

confidence: 99%

An E3 ligase TRIM1 promotes colorectal cancer progression via K63-linked ubiquitination and activation of HIF1α

Shi,

Fang,

et al. 2024

Oncogenesis

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Accumulating studies have shown that E3 ligases play crucial roles in regulating cellular biological processes and signaling pathways during carcinogenesis via ubiquitination. Tripartite-motif (TRIM) ubiquitin E3 ligases consist of over 70 members. However, the clinical significance and their contributions to tumorigenesis remain largely unknown. In this study, we analyzed the RNA-sequencing expression of TRIM E3 ligases in colorectal cancer (CRC) and identified 10 differentially expressed genes, among which TRIM1 expression predicted poor prognosis of CRC patients. We demonstrated that TRIM1 expression is positively associated with CRC pathological stages, and higher expression is positively correlated with infiltrating levels of immune cells and immunotherapy biomarkers. TRIM1 expression promotes the proliferation and migration of colorectal cancer cells in vitro and in vivo. Transcriptional analysis showed that TRIM1 is responsible for metabolism promotion and immune suppression. Mechanistically, we found that TRIM1 binds HIF1α and mediates its K63-linked ubiquitination, which is required for HIF1α nuclear translocation and subsequent activation. Ubiquitination occurs at Lys214 in the loop between the two PAS domains of HIF1α, and mutation of Lys214 severely disturbs the function of HIF1α. Besides, HIF1α ubiquitination enhances its binding with proteins involved in cellular trafficking and nucleocytoplasmic transport pathway. Collectively, our results indicate TRIM1’s role in predicting prognosis and reveal how TRIM1 functions to upregulate HIF1α expression and promote tumor cell proliferation.

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“…Interestingly, the PI3K/AKT pathway also regulates GSDME‐dependent pyroptosis (Yu, Tan, et al, 2022). It may be that the activation of Caspase‐9 is inhibited by AKT, thereby reducing Caspase‐9/3/GSDME axis‐induced pyroptosis (Li, Shi, et al, 2022; Sangawa et al, 2014).…”

Section: Different Types Of Cell Death Cross‐talk With Pi3k/akt Pathwaymentioning

confidence: 99%

Multiple forms of cell death: A focus on the PI3K/AKT pathway

Xu,

Li,

Kang

et al. 2023

Journal Cellular Physiology

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Cell death is a natural biological process that occurs in living organisms. Since 1963, extensive research has shed light on the occurrence, progress, and final outcome of cell death. According to different cell phenotypes, it is classified into different types, including apoptosis, pyroptosis, necroptosis, autophagy, ferroptosis, cuproptosis, and so on. However, regardless of the form of cell death, what we ultimately expect is the disappearance of abnormal cells, such as tumor cells, while normal cells survive. As a result, it is vital to investigate the details of cell death, including death triggers, potent regulators, and executioners. Although significant progress has been made in understanding molecular pathways of cell death, many aspects remain unclear because of the complex regulatory networks in cells. Among them, the phosphoinositide‐3‐kinase (PI3K)/protein kinase B(AKT) pathway is discovered to be a crucial regulator of the cell death process. AKT, as a proto‐oncogene, has become a major focus of attention in the medical community due to its role in regulating a multiplicity of cellular functions counting metabolism, immunity, proliferation, survival, transcription, and protein synthesis. Here, we explored the connection between the PI3K/AKT pathway and cell death, aiming to enhance our comprehension of the mechanism underlying this process. Such knowledge may pave the way for the subsequent development of more effective disease treatments, such as finding suitable targets for drug intervention.

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Aloe-Emodin Induces Mitochondrial Dysfunction and Pyroptosis by Activation of the Caspase-9/3/Gasdermin E Axis in HeLa Cells

Cited by 12 publications

References 42 publications

Exploring the mechanism of aloe-emodin in the treatment of liver cancer through network pharmacology and cell experiments

Exploring the mechanism of aloe-emodin in the treatment of liver cancer through network pharmacology and cell experiments

An E3 ligase TRIM1 promotes colorectal cancer progression via K63-linked ubiquitination and activation of HIF1α

Multiple forms of cell death: A focus on the PI3K/AKT pathway

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