Choline Kinase Alpha Promoted Glioma Development by Activating PI3K/AKT Signaling Pathway

Zou, Yourui; Huang, Ling; Sun, Shibin; Yue, Fangqian; Li, Zhuoqi; Ma, Yue; Ma, Hui

doi:10.1089/cbr.2021.0294

Cited by 8 publications

(4 citation statements)

References 24 publications

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“…4 D). This might indeed be a consequence of Chokα action directly but also due to further metabolic conversion of the end product of the choline pathway, PC, as shown in glioma development [ 60 ], into phosphatidic acid (PA), known as an inducer of several Ras signaling pathways such as PI3K/AKT and ERK-MAPK signaling [ 21 , 54 ]. Indeed, PLD1 and PLD2 enzymes responsible for PC conversion into PA were highly upregulated in hAITL Tfh cells compared to other healthy CD4 T-cell subsets and even to a significantly higher extent as compared to healthy Tfh cells.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of choline metabolism in an angioimmunoblastic T-cell lymphoma preclinical model reveals a new metabolic vulnerability as possible target for treatment

Krug,

Tosolini,

Madji Hounoum

et al. 2024

J Exp Clin Cancer Res

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Background Angioimmunoblastic T-cell lymphoma (AITL) is a malignancy with very poor survival outcome, in urgent need of more specific therapeutic strategies. The drivers of malignancy in this disease are CD4+ follicular helper T cells (Tfh). The metabolism of these malignant Tfh cells was not yet elucidated. Therefore, we decided to identify their metabolic requirements with the objective to propose a novel therapeutic option. Methods To reveal the prominent metabolic pathways used by the AITL lymphoma cells, we relied on metabolomic and proteomic analysis of murine AITL (mAITL) T cells isolated from our established mAITL model. We confirmed these results using AITL patient and healthy T cell expression data. Results Strikingly, the mAITL Tfh cells were highly dependent on the second branch of the Kennedy pathway, the choline lipid pathway, responsible for the production of the major membrane constituent phosphatidylcholine. Moreover, gene expression data from Tfh cells isolated from AITL patient tumors, confirmed the upregulation of the choline lipid pathway. Several enzymes involved in this pathway such as choline kinase, catalyzing the first step in the phosphatidylcholine pathway, are upregulated in multiple tumors other than AITL. Here we showed that treatment of our mAITL preclinical mouse model with a fatty acid oxydation inhibitor, significantly increased their survival and even reverted the exhausted CD8 T cells in the tumor into potent cytotoxic anti-tumor cells. Specific inhibition of Chokα confirmed the importance of the phosphatidylcholine production pathway in neoplastic CD4 + T cells, nearly eradicating mAITL Tfh cells from the tumors. Finally, the same inhibitor induced in human AITL lymphoma biopsies cell death of the majority of the hAITL PD-1high neoplastic cells. Conclusion Our results suggest that interfering with choline metabolism in AITL reveals a specific metabolic vulnerability and might represent a new therapeutic strategy for these patients.

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Section: Discussionmentioning

confidence: 99%

Inhibition of choline metabolism in an angioimmunoblastic T-cell lymphoma preclinical model reveals a new metabolic vulnerability as possible target for treatment

Krug,

Tosolini,

Madji Hounoum

et al. 2024

J Exp Clin Cancer Res

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“…Pharmacological or genetic depletion of CHKA induces cell growth arrest in both in vivo and in vitro experimental models by altering key players in oncogenic cell signaling. On the other hand, the inhibition of cell signaling (e.g., PI3K) inhibits expression of CHKA, highlighting the role of choline kinase in cancer cell transduction and oncogenic metabolic reprogramming [ 10 , 16 , 34 , 35 , 36 ] (and see references therein). This supports the role of bioactive sphingolipids in cancer progression [ 33 ].…”

Section: Discussionmentioning

confidence: 99%

MALAT1 as a Regulator of the Androgen-Dependent Choline Kinase A Gene in the Metabolic Rewiring of Prostate Cancer

Martino

Iorio

Cencioni

et al. 2022

Cancers

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Background. Choline kinase alpha (CHKA), an essential gene in phospholipid metabolism, is among the modulated MALAT1-targeted transcripts in advanced and metastatic prostate cancer (PCa). Methods. We analyzed CHKA mRNA by qPCR upon MALAT1 targeting in PCa cells, which is characterized by high dose-responsiveness to the androgen receptor (AR) and its variants. Metabolome analysis of MALAT1-depleted cells was performed by quantitative High-resolution 1 H-Nuclear Magnetic Resonance (NMR) spectroscopy. In addition, CHKA genomic regions were evaluated by chromatin immunoprecipitation (ChIP) in order to assess MALAT1-dependent histone-tail modifications and AR recruitment. Results. In MALAT1-depleted cells, the decrease of CHKA gene expression was associated with reduced total choline-containing metabolites compared to controls, particularly phosphocholine (PCho). Upon MALAT1 targeting a significant increase in repressive histone modifications was observed at the CHKA intron-2, encompassing relevant AR binding sites. Combining of MALAT1 targeting with androgen treatment prevented MALAT1-dependent CHKA silencing in androgen-responsive (LNCaP) cells, while it did not in hormone-refractory cells (22RV1 cells). Moreover, AR nuclear translocation and its activation were detected by confocal microscopy analysis and ChIP upon MALAT1 targeting or androgen treatment. Conclusions. These findings support the role of MALAT1 as a CHKA activator through putative association with the liganded or unliganded AR, unveiling its targeting as a therapeutic option from a metabolic rewiring perspective.

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“…For example, the c-Src-dependent link between CHKA and EGFR promoted breast cancer cell proliferation and tumorigenesis ( Miyake and Parsons, 2012 ). Down-regulation of CHKA expression elicited the endoplasmic reticulum stress and induced apoptosis via CHOP in breast cancer ( Sanchez-Lopez et al, 2013 ), and it is reported that CHKA could promote glioma development via activating PI3K/AKT pathways ( Zou et al, 2021 ). In this study, the network pharmacology analysis spectacled that CHKA may interact with the P13K/AKT pathway, which is abnormally active in various tumor cells and is closely related to tumor growth, proliferation, and metabolism ( Hoxhaj and Manning, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Dandelion extract inhibits triple-negative breast cancer cell proliferation by interfering with glycerophospholipids and unsaturated fatty acids metabolism

et al. 2022

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Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype with limited treatment options and a poor prognosis. TNBC exists widely reprogrammed lipid metabolism, and its metabolic-associated proteins and oncometabolites are promising as potential therapeutic targets. Dandelion (Taraxacum mongolicum) is a classical herbal medicine used to treat breast diseases based on traditional Chinese medicine theory and was reported to have antitumor effects and lipid regulatory capacities. Our previous study showed that dandelion extract was effective against TNBC. However, whether dandelion extract could regulate the lipid metabolisms of TNBC and exert its antitumor effects via interfering with lipids metabolism remained unclear. In this study, an integrated approach combined with network pharmacology and multi-omics techniques (including proteomics, metabolomics, and lipidomics) was performed to investigate the potential regulatory mechanisms of dandelion extract against TNBC. We first determined the antitumor effects of dandelion extract in vitro and in vivo. Then, network pharmacology analysis speculated the antitumor effects involving various metabolic processes, and the multi-omics results of the cells, tumor tissues, and plasma revealed the changes in the metabolites and metabolic-associated proteins after dandelion extract treatment. The alteration of glycerophospholipids and unsaturated fatty acids were the most remarkable types of metabolites. Therefore, the metabolism of glycerophospholipids and unsaturated fatty acids, and their corresponding proteins CHKA and FADS2, were considered the primary regulatory pathways and biomarkers of dandelion extract against TNBC. Subsequently, experimental validation showed that dandelion extract decreased CHKA expression, leading to the inhibition of the PI3K/AKT pathway and its downstream targets, SREBP and FADS2. Finally, the molecular docking simulation suggested that picrasinoside F and luteolin in dandelion extract had the most highly binding scores with CHKA, indicating they may be the potential CHKA inhibitors to regulate glycerophospholipids metabolisms of TNBC. In conclusion, we confirmed the antitumor effects of dandelion extract against TNBC cells in vitro and demonstrated that dandelion extract could interfere with glycerophospholipids and unsaturated fatty acids metabolism via downregulating the CHKA expression and inhibiting PI3K/AKT/SREBP/FADS2 axis.

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Choline Kinase Alpha Promoted Glioma Development by Activating PI3K/AKT Signaling Pathway

Cited by 8 publications

References 24 publications

Inhibition of choline metabolism in an angioimmunoblastic T-cell lymphoma preclinical model reveals a new metabolic vulnerability as possible target for treatment

Inhibition of choline metabolism in an angioimmunoblastic T-cell lymphoma preclinical model reveals a new metabolic vulnerability as possible target for treatment

MALAT1 as a Regulator of the Androgen-Dependent Choline Kinase A Gene in the Metabolic Rewiring of Prostate Cancer

Dandelion extract inhibits triple-negative breast cancer cell proliferation by interfering with glycerophospholipids and unsaturated fatty acids metabolism

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