Compound Kushen Injection intervenes metabolic reprogramming and epithelial-mesenchymal transition of HCC via regulating β-catenin/c-Myc signaling

Phytomedicine ◽  
2021 ◽  
Vol 93 ◽  
pp. 153781
Author(s):  
Ke-xin Wang ◽  
Guan-hua Du ◽  
Xue-mei Qin ◽  
Li Gao
Keyword(s):  
Epithelial Mesenchymal Transition ◽  
Metabolic Reprogramming ◽  
Mesenchymal Transition ◽  
Compound Kushen Injection

scholarly journals Epithelial–Mesenchymal Transition (EMT) Induced by TGF-β in Hepatocellular Carcinoma Cells Reprograms Lipid Metabolism

2021 ◽  
Vol 22 (11) ◽  
pp. 5543
Author(s):  
Jitka Soukupova ◽  
Andrea Malfettone ◽  
Esther Bertran ◽  
María Isabel Hernández-Alvarez ◽  
Irene Peñuelas-Haro ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Lipid Metabolism ◽  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Aerobic Glycolysis ◽  
Metabolic Reprogramming ◽  
Migration And Invasion ◽  
Metabolic Switch ◽  
Mesenchymal Transition ◽  
Hcc Cells

(1) Background: The transforming growth factor (TGF)-β plays a dual role in liver carcinogenesis. At early stages, it inhibits cell growth and induces apoptosis. However, TGF-β expression is high in advanced stages of hepatocellular carcinoma (HCC) and cells become resistant to TGF-β induced suppressor effects, responding to this cytokine undergoing epithelial–mesenchymal transition (EMT), which contributes to cell migration and invasion. Metabolic reprogramming has been established as a key hallmark of cancer. However, to consider metabolism as a therapeutic target in HCC, it is necessary to obtain a better understanding of how reprogramming occurs, which are the factors that regulate it, and how to identify the situation in a patient. Accordingly, in this work we aimed to analyze whether a process of full EMT induced by TGF-β in HCC cells induces metabolic reprogramming. (2) Methods: In vitro analysis in HCC cell lines, metabolomics and transcriptomics. (3) Results: Our findings indicate a differential metabolic switch in response to TGF-β when the HCC cells undergo a full EMT, which would favor lipolysis, increased transport and utilization of free fatty acids (FFA), decreased aerobic glycolysis and an increase in mitochondrial oxidative metabolism. (4) Conclusions: EMT induced by TGF-β in HCC cells reprograms lipid metabolism to facilitate the utilization of FFA and the entry of acetyl-CoA into the TCA cycle, to sustain the elevated requirements of energy linked to this process.

scholarly journals Role of Metabolic Reprogramming in Epithelial–Mesenchymal Transition (EMT)

2019 ◽  
Vol 20 (8) ◽  
pp. 2042 ◽  
Author(s):  
Hyunkoo Kang ◽  
Hyunwoo Kim ◽  
Sungmin Lee ◽  
HyeSook Youn ◽  
BuHyun Youn
Keyword(s):  
Tumor Progression ◽  
Tumor Cells ◽  
Molecular Mechanisms ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Metabolic Reprogramming ◽  
Metabolic Enzyme ◽  
Diverse Range ◽  
Mesenchymal Transition ◽  
Altered Glucose

Activation of epithelial–mesenchymal transition (EMT) is thought to be an essential step for cancer metastasis. Tumor cells undergo EMT in response to a diverse range of extra- and intracellular stimulants. Recently, it was reported that metabolic shifts control EMT progression and induce tumor aggressiveness. In this review, we summarize the involvement of altered glucose, lipid, and amino acid metabolic enzyme expression and the underlying molecular mechanisms in EMT induction in tumor cells. Moreover, we propose that metabolic regulation through gene-specific or pharmacological inhibition may suppress EMT and this treatment strategy may be applied to prevent tumor progression and improve anti-tumor therapeutic efficacy. This review presents evidence for the importance of metabolic changes in tumor progression and emphasizes the need for further studies to better understand tumor metabolism.

scholarly journals From transcriptomics to metabolomics: Extracellular ATP induces TGF-β-like and TGF-β-independent epithelial mesenchymal transition in lung cancer cells

2021 ◽  
Author(s):  
Maria Evers ◽  
Jingwen Song ◽  
Pratik Shriwas ◽  
Harrison S Greenbaum ◽  
Xiaozhuo Chen
Keyword(s):  
Gene Expression ◽  
Cancer Cells ◽  
Neutralizing Antibodies ◽  
Epithelial Mesenchymal Transition ◽  
A549 Cells ◽  
Extracellular Atp ◽  
Metabolic Reprogramming ◽  
Specific Gene ◽  
Mesenchymal Transition ◽  
Transcriptomic Changes

Abstract Background: Epithelial mesenchymal transition (EMT) is an early process in metastasis. Extracellular ATP (eATP) was shown to play important roles in EMT. However, the mechanisms by which eATP induces EMT and ATP’s relationship to TGF-b, a well-known EMT inducer, are unclear. Key questions include: if and how much EMT-specific gene expression eATP induces and how similar is ATP-induced EMT to TGF-b-induced EMT? We hypothesized that eATP acts as a specific inducer and regulator of EMT at all levels alternative to TGF-b in cancer cells. Methods: As EMT involves changes from gene expression to metabolites, RNAseq and metabolomics analyses were performed on human NSCLC A549 cells treated with either eATP or TGF-b to determine how they induce EMT at transcription and metabolic levels. Bio-functional assays, such as Transwell invasion, intracellular ATP, resazurin cell viability, fluorescence microscopy of filopodia formation, and antibody neutralization / cell rescue, were conducted in more NSCLC cell lines to validate changes identified from RNAseq and metabolomics analyses by confirming the corresponding EMT phenotypic changes.Results: RNAseq analysis shows that eATP significantly enriched expressions of genes involved in EMT temporarily, and similarly but non-identically to TGF-b after 2 and 6 hours of treatment. Eleven genes, with known or unknown functions in EMT, are significantly upregulated by both inducers at both time points, have been identified. Metabolomics analysis revealed eATP induced numerous EMT-related changes in metabolic pathways, including cytoskeleton rearrangement, glycolysis, glutaminolysis, ROS, and individual metabolic changes similar or identical to those induced by TGF-b. eATP-induced transcriptomic changes appeared smaller but earlier than TGF-b. Functional bioassays verified the RNAseq and metabolomics findings that eATP induced earlier and more invasion and formation of filopodia in A549 and H1299 cells, and restored viability of cancer cells treated with TGF-b-neutralizing antibodies. Conclusions: eATP-induced EMT, from gene expression changes and metabolic reprogramming, is similar but non-identical to that induced by TGF-b, and is independent of TGF-b. The smaller but earlier EMT-related changes induced by eATP, compared with TGF-b, could be largely explained by extracellular action of eATP and intracellular activities of macropinocytosis-internalized eATP. These strongly indicate that eATP is an emerging master inducer and regulator of EMT.

scholarly journals Linking Cancer Stem Cell Plasticity to Therapeutic Resistance-Mechanism and Novel Therapeutic Strategies in Esophageal Cancer

Cells ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 1481
Author(s):  
Chenghui Zhou ◽  
Ningbo Fan ◽  
Fanyu Liu ◽  
Nan Fang ◽  
Patrick S. Plum ◽  
...  
Keyword(s):  
Esophageal Cancer ◽  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Epithelial Mesenchymal Transition ◽  
Resistance Mechanism ◽  
Therapy Resistance ◽  
Metabolic Reprogramming ◽  
Current Evidence ◽  
Mesenchymal Transition ◽  
Therapeutic Implications

Esophageal cancer (EC) is an aggressive form of cancer, including squamous cell carcinoma (ESCC) and adenocarcinoma (EAC) as two predominant histological subtypes. Accumulating evidence supports the existence of cancer stem cells (CSCs) able to initiate and maintain EAC or ESCC. In this review, we aim to collect the current evidence on CSCs in esophageal cancer, including the biomarkers/characterization strategies of CSCs, heterogeneity of CSCs, and the key signaling pathways (Wnt/β-catenin, Notch, Hedgehog, YAP, JAK/STAT3) in modulating CSCs during esophageal cancer progression. Exploring the molecular mechanisms of therapy resistance in EC highlights DNA damage response (DDR), metabolic reprogramming, epithelial mesenchymal transition (EMT), and the role of the crosstalk of CSCs and their niche in the tumor progression. According to these molecular findings, potential therapeutic implications of targeting esophageal CSCs may provide novel strategies for the clinical management of esophageal cancer.

scholarly journals Therapy Resistance in Cancers: Phenotypic, Metabolic, Epigenetic and Tumour Microenvironmental Perspectives

2020 ◽  
Vol 20 (18) ◽  
pp. 2190-2206
Author(s):  
Tasnim Zahan ◽  
Plabon K. Das ◽  
Syeda F. Akter ◽  
Rowshanul Habib ◽  
Md. Habibur Rahman ◽  
...  
Keyword(s):  
Cancer Therapy ◽  
Cancer Cells ◽  
Epithelial Mesenchymal Transition ◽  
Cancer Recurrence ◽  
Therapy Resistance ◽  
Metabolic Reprogramming ◽  
Contributing Factors ◽  
Mesenchymal Transition ◽  
Cellular Processes ◽  
Resistance Property

Background: Chemoresistance is a vital problem in cancer therapy where cancer cells develop mechanisms to encounter the effect of chemotherapeutics, resulting in cancer recurrence. In addition, chemotherapy- resistant leads to the formation of a more aggressive form of cancer cells, which, in turn, contributes to the poor survival of patients with cancer. Objective: In this review, we aimed to provide an overview of how the therapy resistance property evolves in cancer cells, contributing factors and their role in cancer chemoresistance, and exemplified the problems of some available therapies. Methods: The published literature on various electronic databases including, Pubmed, Scopus, Google scholar containing keywords cancer therapy resistance, phenotypic, metabolic and epigenetic factors, were vigorously searched, retrieved and analyzed. Results: Cancer cells have developed a range of cellular processes, including uncontrolled activation of Epithelial- Mesenchymal Transition (EMT), metabolic reprogramming and epigenetic alterations. These cellular processes play significant roles in the generation of therapy resistance. Furthermore, the microenvironment where cancer cells evolve effectively contributes to the process of chemoresistance. In tumour microenvironment immune cells, Mesenchymal Stem Cells (MSCs), endothelial cells and cancer-associated fibroblasts (CAFs) contribute to the maintenance of therapy-resistant phenotype via the secretion of factors that promote resistance to chemotherapy. Conclusion: To conclude, as these factors hinder successful cancer therapies, therapeutic resistance property of cancer cells is a subject of intense research, which in turn could open a new horizon to aim for developing efficient therapies.

scholarly journals MicroRNAs: Their Role in Metabolism, Tumor Microenvironment, and Therapeutic Implications in Head and Neck Squamous Cell Carcinoma

Cancers ◽  
2021 ◽  
Vol 13 (22) ◽  
pp. 5604
Author(s):  
Shine-Gwo Shiah ◽  
Sung-Tau Chou ◽  
Jang-Yang Chang
Keyword(s):  
Tumor Microenvironment ◽  
Epithelial Mesenchymal Transition ◽  
Tumor Development ◽  
Cell Communication ◽  
Cell Types ◽  
Metabolic Reprogramming ◽  
Mesenchymal Transition ◽  
Therapeutic Implications ◽  
Rna Molecules ◽  
Non Coding Rna

MicroRNAs (miRNAs) are endogenous small non-coding RNA molecules that negatively regulate gene expression by binding to target mRNAs. Deregulated miRNAs can act as either oncogenic miRNAs or tumor suppressor miRNAs in controlling proliferation, differentiation, apoptosis, metastasis, epithelial–mesenchymal transition, and immune responses, which are all involved in the carcinogenesis process of HNSCC. Recent findings have shown that metabolic reprogramming is an important hallmark of cancer, which is necessary for malignant transformation and tumor development. Some reprogrammed metabolisms are believed to be required for HNSCC against an unfavorable tumor microenvironment (TME). The TME is composed of various cell types embedded in the altered extracellular matrix, among which exosomes, secreted by cancer cells, are one of the most important factors. Tumor-derived exosomes reshape the tumor microenvironment and play a crucial role in cell-to-cell communication during HNSCC development. Exosomes encapsulate many biomolecules, including miRNAs, circulate in body fluids, and can transmit intercellular regulatory messages to nearby and distant sites, which indicates that exosomal miRNAs have the potential to become non-invasive biomarkers. This review aims to clarify the functions of diverse miRNAs in HNSCC metabolic reprogramming and tumor-derived exosomes. In addition, it also emphasizes the potential role of miRNA as a biomarker in the diagnosis, prognosis, and treatment of HNSCC cancer.

scholarly journals Short-Term and Long-Term Carcinogenic Effects of Food Contaminants (4-Hydroxynonenal and Pesticides) on Colorectal Human Cells: Involvement of Genotoxic and Non-Genomic Mechanisms

Cancers ◽  
2021 ◽  
Vol 13 (17) ◽  
pp. 4337
Author(s):  
Liana C. Arnaud ◽  
Thierry Gauthier ◽  
Augustin Le Naour ◽  
Saleha Hashim ◽  
Nathalie Naud ◽  
...  
Keyword(s):  
Cell Lines ◽  
Epithelial Mesenchymal Transition ◽  
Ectopic Expression ◽  
Metabolic Reprogramming ◽  
Colorectal Carcinogenesis ◽  
Lipid Peroxidation Product ◽  
Food Contaminants ◽  
Promoting Effect ◽  
Mesenchymal Transition

To investigate environmental impacts upon colorectal carcinogenesis (CRC) by diet, we assessed two western diet food contaminants: 4-hydroxynonenal (HNE), a major lipid peroxidation product neoformed during digestion, and a mixture of pesticides. We used human colonic cell lines ectopically eliciting varied genetic susceptibilities to CRC: the non-transformed human epithelial colonic cells (HCECs) and their five isogenic cell lines with the loss of APC (Adenomatous polyposis coli) and TP53 (Tumor protein 53) and/or ectopic expression of mutated KRAS (Kristen-ras). These cell lines have been exposed for either for a short time (2–24 h) or for a long period (3 weeks) to 1 µM HNE and/or 10 µM pesticides. After acute exposure, we did not observe any cytotoxicity or major DNA damage. However, long-term exposure to pesticides alone and in mixture with HNE induced clonogenic transformation in normal HCECs, as well as in cells representing later stages of carcinogenesis. It was associated with genotoxic and non-genomic mechanisms (cell growth, metabolic reprogramming, cell mobility and epithelial-mesenchymal transition) depending on genetic susceptibility. This study demonstrated a potential initiating and promoting effect of food contaminants on CRC after long-term exposure. It supports that these contaminants can accelerate carcinogenesis when mutations in oncogenes or tumor suppressor genes occur.

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