Oncogenic KRAS induces arginine auxotrophy and confers a therapeutic vulnerability to SLC7A1 inhibition in non-small cell lung cancer

Cancer Research, Journal Year: 2024, Volume and Issue: 84(12), P. 1963 - 1977

Published: March 19, 2024

The urea cycle is frequently rewired in cancer cells to meet the metabolic demands of cancer. Elucidation underlying mechanism by which oncogenic signaling mediates reprogramming could help identify targetable vulnerabilities. In this study, we discovered that activation KRAS non-small cell lung (NSCLC) silenced expression argininosuccinate synthase 1 (ASS1), a enzyme catalyzes production arginine from aspartate and citrulline, thereby diverted utilization pyrimidine synthesis high demand for DNA replication. Specifically, facilitated hypoacetylated state promoter region ASS1 gene histone deacetylase 3-dependent manner, turn impeded recruitment c-MYC transcription. suppression KRAS-mutant NSCLC impaired biosynthesis rendered dependency on transmembrane transporter SLC7A1 import extracellular arginine. Depletion both patient-derived organoid xenograft models inhibited KRAS-driven growth. Together, these findings uncover role rewiring metabolism SLC7A1-mediated uptake as therapeutic vulnerability treating NSCLC.

Language: Английский

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How Warburg-Associated Lactic Acidosis Rewires Cancer Cell Energy Metabolism to Resist Glucose Deprivation

Cancers, Journal Year: 2023, Volume and Issue: 15(5), P. 1417 - 1417

Published: Feb. 23, 2023

Lactic acidosis, a hallmark of solid tumour microenvironment, originates from lactate hyperproduction and its co-secretion with protons by cancer cells displaying the Warburg effect. Long considered side effect metabolism, lactic acidosis is now known to play major role in physiology, aggressiveness treatment efficiency. Growing evidence shows that it promotes cell resistance glucose deprivation, common feature tumours. Here we review current understanding how extracellular acting as combination enzymatic inhibitors, signal, nutrient, switch metabolism an oxidative metabolic phenotype, which allows withstand makes promising anticancer target. We also discuss about acidosis’ could be integrated whole-tumour what perspectives opens up for future research.

Language: Английский

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Elevated serum β-hydroxybutyrate, a circulating ketone metabolite, accelerates colorectal cancer proliferation and metastasis via ACAT1

Oncogene, Journal Year: 2023, Volume and Issue: 42(23), P. 1889 - 1899

Published: April 25, 2023

Language: Английский

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Phenotypic profiling of solute carriers characterizes serine transport in cancer

Nature Metabolism, Journal Year: 2023, Volume and Issue: 5(12), P. 2148 - 2168

Published: Dec. 8, 2023

Abstract Serine is a vital amino acid in tumorigenesis. While cells can perform de novo serine synthesis, most transformed rely on uptake to meet their increased biosynthetic requirements. Solute carriers (SLCs), family of transmembrane nutrient transport proteins, are the gatekeepers acquisition and exchange mammalian emerging as anticancer therapeutic targets; however, SLCs that mediate cancer remain unknown. Here we an arrayed RNAi screen SLC-encoding genes while monitoring consumption cell proliferation colorectal using metabolomics high-throughput imaging. We identify SLC6A14 SLC25A15 major cytoplasmic mitochondrial transporters, respectively. also observe SLC12A4 facilitates uptake. Dual targeting either or diminishes growth vitro vivo, particularly with compromised biosynthesis. Our results provide insight into mechanisms contribute intracellular handling.

Language: Английский

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Comprehensive analyses of solute carrier family members identify SLC12A2 as a novel therapy target for colorectal cancer

Scientific Reports, Journal Year: 2024, Volume and Issue: 14(1)

Published: Feb. 23, 2024

Abstract As the largest transporter family impacting on tumor genesis and development, prognostic value of solute carrier (SLC) members has not been elucidated in colorectal cancer (CRC). We aimed to identify a signature from SLC comprehensively analyze their roles CRC. Firstly, we downloaded transcriptome data clinical information CRC samples GEO (GSE39582) TCGA as training testing dataset, respectively. extracted expression matrix genes established model by univariate multivariate Cox regression. Afterwards, low-risk high-risk group were identified. Then, differences prognosis traits, features, characteristics, immune infiltration drug sensitivity between two groups explored. Furthermore, molecular subtyping was also implemented non-negative factorization (NMF). Finally, studied screened tissues normal well investigated role SLC12A2 loss function gain function. result, developed risk based 6-SLC (SLC39A8, SLC2A3, SLC39A13, SLC35B1, SLC4A3, SLC12A2). Both sets, patients had poorer more advanced pathological stage. What’s more, enriched with progression signatures infiltration. Two showed different sensitivity. On other hand, distinct subclasses (C1 C2) identified 6 genes. C1 subtype worse prognosis. found validated that steadily upregulated A loss-of-function study knockdown restrained proliferation stemness cells while gain-of-function contrary results. Hence, provided gene for prediction patients. At same time, could promote CRC, which may serve potential therapeutic target.

Language: Английский

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Unconventional Functions of Amino Acid Transporters: Role in Macropinocytosis (SLC38A5/SLC38A3) and Diet-Induced Obesity/Metabolic Syndrome (SLC6A19/SLC6A14/SLC6A6)

Biomolecules, Journal Year: 2022, Volume and Issue: 12(2), P. 235 - 235

Published: Jan. 31, 2022

Amino acid transporters are expressed in mammalian cells not only the plasma membrane but also intracellular membranes. The conventional function of these is to transfer their amino substrates across lipid bilayer; direction dictated by combined gradients for and co-transported ions (Na+, H+, K+ or Cl−) membrane. In cases electrogenic transporters, potential contributes transfer. addition this expected traditional function, several unconventional functions known some transporters. This includes role signaling, regulation acid–base balance, entry viruses into cells. Such expand biological roles beyond logical homeostasis. recent years, two additional biochemical/metabolic processes regulated certain have come be recognized: macropinocytosis obesity. adds repertoire that controlled health disease. present review, we highlight unusual involvement selective (SLC38A5/SLC38A3) diet-induced obesity/metabolic syndrome (SLC6A19/SLC6A14/SLC6A6).

Language: Английский

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Advancing drug discovery through assay development: a survey of tool compounds within the human solute carrier superfamily

Frontiers in Pharmacology, Journal Year: 2024, Volume and Issue: 15

Published: July 9, 2024

With over 450 genes, solute carriers (SLCs) constitute the largest transporter superfamily responsible for uptake and efflux of nutrients, metabolites, xenobiotics in human cells. SLCs are associated with a wide variety diseases, including cancer, diabetes, metabolic neurological disorders. They represent an important therapeutic target class that remains only partly exploited as therapeutics scarce. Additionally, many small molecules reported literature to poorly characterized. Both features may be due difficulty developing SLC transport assays fulfill quality criteria high-throughput screening. Here, we report one main limitations hampering assay development within RESOLUTE consortium: lack resource providing high-quality information on tool compounds. To address this, provide systematic annotation compounds targeting SLCs. We first overview assays. Next, present list SLC-targeting collected from public databases; found most data sources lacked specificity data. Finally, experimental tests 19 selected against panel 13 seven different families. Except few inhibitors, which were active unrelated SLCs, tested inhibitors demonstrated high selectivity their targets. make this knowledge easily accessible scientific community, created interactive dashboard displaying web portal (https://re-solute.eu). anticipate our open-access resources will support future drug discovery campaigns

Language: Английский

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Potent Inhibition of Macropinocytosis by Niclosamide in Cancer Cells: A Novel Mechanism for the Anticancer Efficacy for the Antihelminthic

Cancers, Journal Year: 2023, Volume and Issue: 15(3), P. 759 - 759

Published: Jan. 26, 2023

Niclosamide, a drug used to treat tapeworm infection, possesses anticancer effects by interfering with multiple signaling pathways. Niclosamide also causes intracellular acidification. We have recently discovered that the amino acid transporter SLC38A5, an acid-dependent Na+/H+ exchanger, activates macropinocytosis in cancer cells via acid-induced alkalinization. Therefore, we asked whether niclosamide will block basal and SLC38A5-mediated monitored pancreatic breast using TMR-dextran function of SLC38A5 measuring Li+-stimulated serine uptake. The peptide activity was measured uptake glycylsarcosine. Treatment caused blocked serine-induced differential potency, EC50 ~5 μM for former ~0.4 latter. increased potency acid-mediated is due direct inhibition addition ability cause inhibited H+-coupled transporter. conclude induces nutrient starvation blocking macropinocytosis, These studies uncover novel, hitherto unknown, mechanisms efficacy this antihelminthic.

Language: Английский

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Plasma metabolomics of oral squamous cell carcinomas based on NMR and MS approaches provides biomarker identification and survival prediction

Scientific Reports, Journal Year: 2023, Volume and Issue: 13(1)

Published: May 26, 2023

Abstract Metabolomics has proven to be an important omics approach understand the molecular pathways underlying tumour phenotype and identify new clinically useful markers. The literature on cancer illustrated potential of this as a diagnostic prognostic tool. present study aimed analyse plasma metabolic profile patients with oral squamous cell carcinoma (OSCC) controls compare metastatic primary tumours at different stages subsites using nuclear magnetic resonance mass spectrometry. To our knowledge, is only report that compared replicates collected in diverse institutions times these methodologies. Our results showed OSCC suggestive abnormal ketogenesis, lipogenesis energy metabolism, which already early phases but more evident advanced disease. Reduced levels several metabolites were also associated unfavorable prognosis. observed metabolomic alterations may contribute inflammation, immune response inhibition growth, explained by four nonexclusive views—differential synthesis, uptake, release, degradation metabolites. interpretation assimilates views cross talk between neoplastic normal cells microenvironment or distant anatomical sites, connected biofluids, signalling molecules vesicles. Additional population samples evaluate details processes lead discovery biomarkers novel strategies for prevention treatment.

Language: Английский

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Mass spectrometry-based methods for investigating the dynamics and organization of the surfaceome: exploring potential clinical implications

Expert Review of Proteomics, Journal Year: 2024, Volume and Issue: 21(1-3), P. 99 - 113

Published: Feb. 1, 2024

Introduction Cell-surface proteins are extremely important for many cellular events, such as regulating cell-cell communication and cell-matrix interactions. Aberrant alterations in surface protein expression, modification (especially glycosylation), interactions directly related to human diseases. Systematic investigation of advances our understanding functions, activities, disease mechanisms, which will lead identifying biomarkers drug targets.

Language: Английский

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