Lactic acidosis promotes aggressive features of cholangiocarcinoma cells via upregulating ALDH1A3 expression through EGFR axis

Thamrongwaranggoon, Ubonrat; Detarya, Marutpong; Seubwai, Wunchana; Saengboomee, Charupong; Hino, Shinjiro; Koga, Tomoaki; Nakao, Mitsuyoshi; Wongkham, Sopit

doi:10.1016/j.lfs.2022.120648

Cited by 7 publications

(6 citation statements)

References 51 publications

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“…Loss of function of EGFR and other protein tyrosine kinases or abnormal activity or cell localization of key factors in their related signaling pathways can cause tumors, diabetes, immune deficiency, and cardiovascular diseases. EGFR is a target involved in non-smallcell, lung cancer, lung adenocarcinoma, and cholangiocarcinoma [26][27][28]. ESR1, an estrogen receptor, affects cell proliferation and differentiation in target tissues, participating in the pathological process including breast cancer, endometrial cancer, and osteoporosis [29,30].…”

Section: Discussionmentioning

confidence: 99%

Network Pharmacology-Integrated Molecular Docking Reveals the Expected Anticancer Mechanism of Picrorhizae Rhizoma Extract

Zhao

Cai

et al. 2022

BioMed Research International

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This study sought to explore the anticancer mechanism of Picrorhizae Rhizoma (PR) extract based on network pharmacology and molecular docking. The potential chemicals of PR were screened through the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database and relevant literatures. Corresponding targets of active ingredients were found with the help of the UniProtKB database, and therapeutic targets for cancer action were screened with the help of the GeneCards database. We used Cytoscape software to construct the compound-target-pathway network of PR extract. We utilized the STRING database to obtain the protein-protein interaction (PPI) network. We used DAVID database combining Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Finally, molecular docking was employed for initial efficacy checking. We have identified 16 potential active components of PR through screening, involving 112 disease action targets. Utilizing the GeneCards database, 112 intersecting targets between PR extract and cancer were found, which mainly exerts anticancer effects by regulating tumor necrosis factor (TNF), recombinant caspase 3 (CASP3), c-Jun NH2-terminal kinase (JNK)/JUN, epidermal growth factor receptor (EGFR), and estrogen receptor-1 (ESR1) with some other target genes and pathways associated with cancer. The major anticancer species are prostate cancer, colorectal cancer, small cell lung cancer, etc. In the molecular docking study, herbactin had a strong affinity for TNF. Based on network pharmacology and molecular docking studies, PR and their compounds have demonstrated potential anticancer activities against several key targets. Our preliminary findings provide a strong foundation for further experiments with PR constituents.

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Section: Discussionmentioning

confidence: 99%

Network Pharmacology-Integrated Molecular Docking Reveals the Expected Anticancer Mechanism of Picrorhizae Rhizoma Extract

Zhao

Cai

et al. 2022

BioMed Research International

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“…To verify the expression level of THBS1 in CCA tissues, the THBS1 protein was investigated in 20 CCA tissues by immunohistochemistry. As LDHA implies LA in tumor tissues, 14 LDHA immunohistochemistry was performed in the same set of CCA tissues. A positive signal for THBS1 and LDHA was observed in the cytoplasm of hyperplastic/dysplastic bile ducts and CCA but not in the adjacent non‐tumor bile duct tissues (Figure 6A ).…”

Section: Resultsmentioning

confidence: 99%

“…To generate LA conditions, CCA cells were cultured in LA medium, as described previously (Figure 1A ). 14 Two LA conditions were used in this study: SLA and LLA. For SLA, cells in LG‐DMEM were replaced with LA medium and cultured for 24 h. For LLA, we allowed the cells to become acclimated to the LA condition by gradually increasing the lactate concentration (6.25, 12.5, 18.75, and 25 mM).…”

Section: Methodsmentioning

confidence: 99%

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Lactic acidosis induces metabolic and phenotypic reprogramming in cholangiocarcinoma cells via the upregulation of thrombospondin‐1

et al. 2023

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The high glycolytic activity of cancer cells leads to lactic acidosis (LA) in the tumor microenvironment. LA is not merely a consequence of metabolic activities but also has functional roles in metabolic reprogramming and cancer progression. Cholangiocarcinoma (CCA) cells exhibit a high dependency on glycolysis for survival and growth, but the specific effects of LA on cellular characteristics remain unknown. Here, we demonstrate that long‐term LA (LLA) reprograms the metabolic phenotype of CCA cells from glycolytic to oxidative and enhances their migratory activity. In CCA cell culture, short‐term LA (24 h) showed a growth inhibitory effect, while extended LA exposure for more than 2 weeks (LLA) led to enhanced cell motility. Coincidentally, LLA enhanced the respiratory capacity with an increase in mitochondrial mass. Inhibition of mitochondrial function abolished LLA‐induced cell motility, suggesting that metabolic remodeling affects the phenotypic outcomes. RNA‐sequencing analysis revealed that LLA upregulated genes associated with cell migration and epithelial–mesenchymal transition (EMT), including thrombospondin‐1 (THBS1), which encodes a pro‐EMT‐secreted protein. Inhibition of THBS1 resulted in the suppression of both LLA‐induced cell motility and respiratory capacity. Moreover, high THBS1 expression was associated with poor survival in patients with CCA. Collectively, our study suggests that the increased expression of THBS1 by LLA promotes phenotypic alterations, leading to CCA progression.

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“…83 In addition, lactic acidosis has been shown to upregulate epidermal growth factor receptor and ALDH1A3 expression, leading to the aggressiveness of CCA cells. 84 Given the fact that ALDH1A3 is protumorigenic, it is not surprising that this gene displayed a 3.58-fold upregulation in CCA (Table 2). We also found upregulation of the ALDH16A1 (3.83fold), ALDH1L2 (7.24-fold), ALDH3B1 (8.47-fold), ALDH3B2 (46-fold), and ALDH18A1 genes (3.13-fold) in CCA tumors (Table 2).…”

Section: Aldhs and Ccamentioning

confidence: 99%

Acetaldehyde Dehydrogenases in Liver Zonation and Liver Cancer

Jin-Smith¹,

Jn-Simon²,

Basha³

et al. 2023

Gene Expr

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ALDHs consist of 24 families in the eukaryotic ALDH gene superfamily. Nineteen of them are found in the human genome and belong to the ALDH1-9, ALDH16, and ALDH18 families. 1 There are six isotype genes in the ALDH1 family (ALDH1A1, ALDH1A2, ALDH1A3, ALDH1B1, ALDH1L1, and ALDH1L2). Among them, ALDH1A1, ALDH1A2, and ALDH1A3 encode cytosolic enzymes that oxidize retinal and aliphatic aldehydes. ALDH1A1 protein binds to retinaldehyde in great affinity and has been considered a major retinoid acid-metabolizing enzyme. 2 Cytosolic ALDH1A1 also plays a role in acetaldehyde oxidation and alcohol preference

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Lactic acidosis promotes aggressive features of cholangiocarcinoma cells via upregulating ALDH1A3 expression through EGFR axis

Cited by 7 publications

References 51 publications

Network Pharmacology-Integrated Molecular Docking Reveals the Expected Anticancer Mechanism of Picrorhizae Rhizoma Extract

Network Pharmacology-Integrated Molecular Docking Reveals the Expected Anticancer Mechanism of Picrorhizae Rhizoma Extract

Lactic acidosis induces metabolic and phenotypic reprogramming in cholangiocarcinoma cells via the upregulation of thrombospondin‐1

Acetaldehyde Dehydrogenases in Liver Zonation and Liver Cancer

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