Lysine Deprivation Induces AKT-AADAT Signaling and Overcomes EGFR-TKIs Resistance in EGFR-Mutant Non-Small Cell Lung Cancer Cells

Hsu, Chia Chi; Yang, Albert Ying Po; Chen, Jui Yi; Tsai, Hui Lien; Lin, Shu Heng; Tai, Pei Chen; Huang, Ming; Hsu, Wen-Ling; Lin, Anya Maan Yuh; Yang, James Chih Hsin

doi:10.3390/cancers13020272

Cited by 8 publications

(4 citation statements)

References 48 publications

(62 reference statements)

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“…This metabolite is a potential modulator of glucose homeostasis; moreover, it has been identified as a marker of tumor aggressiveness in glioblastoma [ 43 ] and is altered in TNBC cell lines after administration of PARP inhibitor Veliparib [ 44 ]. In fact, it has been demonstrated that lysine metabolism is a relevant process in cancer [ 45 , 46 ]. Other interesting findings are the differences in phenylalanine production ( p -value = 8.36 × 10 −20 ), a protective amino acid against cancer [ 47 ] or capric acid ( p -value = 2.21 × 10 −12 ), a non-competitive AMPA receptor antagonist, responsible for the mitochondrial proliferation, that has been associated with overall breast cancer risk [ 48 ].…”

Section: Discussionmentioning

confidence: 99%

Crosstalk between Metabolite Production and Signaling Activity in Breast Cancer

Çubuk

Loucera

Peña‐Chilet

et al. 2023

IJMS

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The reprogramming of metabolism is a recognized cancer hallmark. It is well known that different signaling pathways regulate and orchestrate this reprogramming that contributes to cancer initiation and development. However, recent evidence is accumulating, suggesting that several metabolites could play a relevant role in regulating signaling pathways. To assess the potential role of metabolites in the regulation of signaling pathways, both metabolic and signaling pathway activities of Breast invasive Carcinoma (BRCA) have been modeled using mechanistic models. Gaussian Processes, powerful machine learning methods, were used in combination with SHapley Additive exPlanations (SHAP), a recent methodology that conveys causality, to obtain potential causal relationships between the production of metabolites and the regulation of signaling pathways. A total of 317 metabolites were found to have a strong impact on signaling circuits. The results presented here point to the existence of a complex crosstalk between signaling and metabolic pathways more complex than previously was thought.

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Section: Discussionmentioning

confidence: 99%

Crosstalk between Metabolite Production and Signaling Activity in Breast Cancer

Çubuk

Loucera

Peña‐Chilet

et al. 2023

IJMS

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“…We found that the trained macrophages in PVM-OVA group had a large number of metabolites, such as amino acids, phospholipids, isocitrate, and so on. Amino acids play a vital role in the physiological/metabolic functions of humans, and the abnormal metabolism of amino acids is related to many human diseases, including asthma ( 52 ) and cancer ( 53 ). The increase of certain amino acids such as cysteine and serine in asthmatic patients leads directly or indirectly to the onset of asthma ( 54 ).…”

Section: Discussionmentioning

confidence: 99%

Proline metabolism reprogramming of trained macrophages induced by early respiratory infection combined with allergen sensitization contributes to development of allergic asthma in childhood of mice

et al. 2022

Front. Immunol.

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BackgroundInfants with respiratory syncytial virus (RSV)-associated bronchiolitis are at increased risk of childhood asthma. Recent studies demonstrated that certain infections induce innate immune memory (also termed trained immunity), especially in macrophages, to respond more strongly to future stimuli with broad specificity, involving in human inflammatory diseases. Metabolic reprogramming increases the capacity of the innate immune cells to respond to a secondary stimulation, is a crucial step for the induction of trained immunity. We hypothesize that specific metabolic reprogramming of lung trained macrophages induced by neonatal respiratory infection is crucial for childhood allergic asthma.ObjectiveTo address the role of metabolic reprogramming in lung trained macrophages induced by respiratory virus infection in allergic asthma.MethodsNeonatal mice were infected and sensitized by the natural rodent pathogen Pneumonia virus of mice (PVM), a mouse equivalent strain of human RSV, combined with ovalbumin (OVA). Lung CD11b+ macrophages in the memory phase were re-stimulated to investigate trained immunity and metabonomics. Adoptive transfer, metabolic inhibitor and restore experiments were used to explore the role of specific metabolic reprogramming in childhood allergic asthma.ResultsPVM infection combined with OVA sensitization in neonatal mice resulted in non-Th2 (Th1/Th17) type allergic asthma following OVA challenge in childhood of mice. Lung CD11b+ macrophages in the memory phage increased, and showed enhanced inflammatory responses following re-stimulation, suggesting trained macrophages. Adoptive transfer of the trained macrophages mediated the allergic asthma in childhood. The trained macrophages showed metabolic reprogramming after re-stimulation. Notably, proline biosynthesis remarkably increased. Inhibition of proline biosynthesis suppressed the development of the trained macrophages as well as the Th1/Th17 type allergic asthma, while supplement of proline recovered the trained macrophages as well as the allergic asthma.ConclusionProline metabolism reprogramming of trained macrophages induced by early respiratory infection combined with allergen sensitization contributes to development of allergic asthma in childhood. Proline metabolism could be a well target for prevention of allergic asthma in childhood.

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“…Unfortunately, previous studies revealed that genomic alterations of driver genes are infrequent in LEC 4,16,17 . In addition to genomic alterations, aspects of the tumor microenvironment such as the immune microenvironment, molecules, and nutrient availability have been reported to correlate with the clinical outcome and drug sensitivity in this particular type of lung cancer [18][19][20][21] . However, the immune microenvironment of LEC is still largely unknown, and its relationship with clinical outcomes is intriguing to investigate.…”

Section: Introductionmentioning

confidence: 99%

Spatial Proximity of Tumor Infiltrating Immune Cells Uncovers a Novel Insight in Pulmonary Lymphoepithelial Carcinoma

Hsu

Hsieh

et al. 2022

Preprint

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Pulmonary lymphoepithelial carcinoma (LEC) is a rare type of lung cancer. Though the clinical outcomes of patients with LEC are better than those for patients with other types of lung cancer, tumors frequently recur. Evidence has indicated that the immune microenvironment factors may predict outcome of cancer therapy; however, the composition of immune microenvironment in LEC remains largely unknown. We investigated the association between the immune microenvironment of LEC by using multiplex immunohistochemical staining. The densities of each tumor-infiltrating immune cell type and the amount of infiltrating immune cells spatially proximal to the closet tumor cell were analyzed. Although there was no significant correlation between the clinical outcome of LEC and the density of each tumor-infiltrating immune cell type, we found that the amount of CD4 + T lymphocyte proximal to tumor positively trended to longer disease-free survival in LEC. Additionally, the PD-L1 tumor proportion score was highly correlated with the amount of CD8 + T lymphocyte proximal to tumor, suggesting that immunotherapy might be beneficial for LEC patients. The spatial proximity of tumor-infiltrating immune cell measurement is useful for investigating the tumor-immune cells interaction. The spatial proximity of tumor-infiltrating CD4 + T lymphocytes might serve as a good prognostic factor for LEC.

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Lysine Deprivation Induces AKT-AADAT Signaling and Overcomes EGFR-TKIs Resistance in EGFR-Mutant Non-Small Cell Lung Cancer Cells

Cited by 8 publications

References 48 publications

Crosstalk between Metabolite Production and Signaling Activity in Breast Cancer

Crosstalk between Metabolite Production and Signaling Activity in Breast Cancer

Proline metabolism reprogramming of trained macrophages induced by early respiratory infection combined with allergen sensitization contributes to development of allergic asthma in childhood of mice

Spatial Proximity of Tumor Infiltrating Immune Cells Uncovers a Novel Insight in Pulmonary Lymphoepithelial Carcinoma

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