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Inhibition of L-type amino acid transporter 1 induces disruption of cancer amino acid homeostasis with altered cellular signals

ABSTRACT: This study characterized the changes of phosphorylation signaling cascades induced by LAT1 inhibition in three cell lines of biliary tract cancer treated with LAT1 specific inhibitor JPH203 for 15 and 30 min. Immobilized metal affinity chromatography and liquid chromatography-tandem mass spectrometry with MS2-based quantitation of tandem mass tag were utilized.

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Yoshikatsu Kanai

PROVIDER: PXD034276 | JPOST Repository | Wed May 24 00:00:00 BST 2023

REPOSITORIES: jPOST

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			Action	DRS
	20200704_KKU100_JPH_15m_IMAC_TMT_01_5p.raw	Raw
	20200704_KKU100_JPH_15m_IMAC_TMT_02_7p.raw	Raw
	20200704_KKU100_JPH_15m_IMAC_TMT_03_9p.raw	Raw
	20200704_KKU100_JPH_15m_IMAC_TMT_04_11p.raw	Raw
	20200704_KKU100_JPH_15m_IMAC_TMT_05_13p.raw	Raw

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Publications

Phosphoproteomics revealed cellular signals immediately responding to disruption of cancer amino acid homeostasis induced by inhibition of L-type amino acid transporter 1.

Okanishi Hiroki H Ohgaki Ryuichi R Xu Minhui M Endou Hitoshi H Kanai Yoshikatsu Y

Cancer & metabolism 20221110 1

<h4>Background</h4>Cancer-upregulated L-type amino acid transporter 1 (LAT1; SLC7A5) supplies essential amino acids to cancer cells. LAT1 substrates are not only needed for cancer rapid growth, but involved in cellular signaling. LAT1 has been proposed as a potential target for cancer treatment-its inhibitor, JPH203, is currently in clinical trials and targets biliary tract cancer (BTC). Here, we revealed to what extent LAT1 inhibitor affects intracellular amino acid content and what kind of cel ...[more]

PMID: 36357940

Similar Datasets

Integrated proteomics and phosphoproteomics analyses reveal the broad and complex influence by inhibition of L-type amino acid transporter-1 in biliary tract carcinoma cells

Project description:To characterize the changes of phosphorylation signaling cascades and protein expressions induced by LAT1 inhibition in 4 cell lines of biliary tract cancer treated with LAT1 specific inhibitor JPH203, immobilized metal affinity chromatography and liquid chromatography-tandem mass spectrometry with MS2-based quantitation of tandem mass tag were utilized.

2020-12-25 | PXD019458 | JPOST Repository

AKT signaling mediates the cellular adaptation to LAT1 pharmacologic inhibition in pancreatic ductal adenocarcinoma.

Project description:To characterize the changes of phosphorylation signaling cascades induced by LAT1 inhibition in MIA PaCa-2 cells treated with LAT1 specific inhibitor JPH203, immobilized metal affinity chromatography and liquid chromatography-tandem mass spectrometry with MS2-based quantitation of tandem mass tag were utilized. To characterize the changes of protein expressions induced by LAT1 inhibition and AKT inhibition in MIA PaCa-2 cells exposed to LAT1 specific inhibitor JPH203 with or without AKT inhibitor MK-2206, immobilized metal affinity chromatography and liquid chromatography-tandem mass spectrometry with MS2-based quantitation of tandem mass tag were utilized.

2024-04-15 | PXD034389 | JPOST Repository

Inhibition of growth factor signaling prevents SARS-CoV-2 replication

Project description:Caco-2 cells were mock-infected or infected with SARS-CoV-2 patient isolates (in biological quintruplicates) for one hour, washed, and incubated for 24 hours before cell harvest. Extracted proteins were digested and split to 1) carry out whole-cell proteomics of a tandem mass tag (TMT) 10-plex samples using liquid chromatography synchronous precursor selection mass spectromety (LC-SPS-MS3), or 2) use Fe-NTA phosphopeptide enrichment (achieving 98% enrichment) for phospho proteome analyses of a TMT 10-plex analyzed by LC-MS2 First 5 channels = control Last 5 channels = infected

2020-05-15 | PXD018357 | Pride

Integration of Metabolomics and Transcriptomics Reveals HDL-Driven Biliary Reverse Cholesterol Transport Involved in the Antiatherogenic Effect of San-wei-tan-xiang Capsule

Project description:Biliary reverse cholesterol transport (RCT) plays a crucial role in cholesterol clearance and regulation of atherogenesis. San-wei-tan-xiang capsule (SWTX), a traditional Chinese medicine, has shown potential in inhibiting atherogenesis by increasing high-density lipoprotein (HDL) cholesterol levels and promoting macrophage-mediated cholesterol efflux. However, the specific role of HDL-driven cholesterol metabolism in the anti-atherogenic effects of SWTX remains unclear. In this study, liquid chromatography coupled with tandem mass spectrometry was used to analyze the circulating metabolic profile, and RNA sequencing was performed on liver samples from ApoE−/− mice fed a cholesterol-enriched diet. We found that SWTX treatment induced significantly differential expression of metabolites and genes involved in cholesterol and lipid metabolism, as well as bile secretion pathways, which are critical for HDL-driven biliary RCT. Furthermore, alterations in L-carnitine and choline metabolism induced by SWTX treatment was involved in the atheroprotective effects of SWTX. Notably, SWTX treatment led to a significant increase in the expression of cholesterol 7α-hydroxylase (CYP7A1), a key enzyme involved in bile acid synthesis during atherogenesis. Additionally, the expression of CYP7A1 and CYP7A1-mediated bile acid secretion were enhanced by the addition of choline in hepatic cells, suggesting that SWTX-induced elevation of choline metabolic products may contribute to the upregulation of CYP7A1 and CYP7A1-mediated biliary RCT. Overall, SWTX demonstrated its ability to attenuate atherosclerotic plaque formation, which can be attributed to alterations in carnitine and choline metabolism, as well as the modulation of CYP7A1-mediated HDL-driven biliary RCT.

2024-06-12 | GSE236672 | GEO

Amino acid coevolution induces an evolutionary Stokes shift.

Project description:The process of amino acid replacement in proteins is context-dependent, with substitution rates influenced by local structure, functional role, and amino acids at other locations. Predicting how these differences affect replacement processes is difficult. To make such inference easier, it is often assumed that the acceptabilities of different amino acids at a position are constant. However, evolutionary interactions among residue positions will tend to invalidate this assumption. Here, we use simulations of purple acid phosphatase evolution to show that amino acid propensities at a position undergo predictable change after an amino acid replacement at that position. After a replacement, the new amino acid and similar amino acids tend to become gradually more acceptable over time at that position. In other words, proteins tend to equilibrate to the presence of an amino acid at a position through replacements at other positions. Such a shift is reminiscent of the spectroscopy effect known as the Stokes shift, where molecules receiving a quantum of energy and moving to a higher electronic state will adjust to the new state and emit a smaller quantum of energy whenever they shift back down to the original ground state. Predictions of changes in stability in real proteins show that mutation reversals become less favorable over time, and thus, broadly support our results. The observation of an evolutionary Stokes shift has profound implications for the study of protein evolution and the modeling of evolutionary processes.

| S-EPMC3361410 | biostudies-literature

The amino acid substitution affects cellular response to mistranslation.

Project description:Mistranslation, the misincorporation of an amino acid not specified by the "standard" genetic code, occurs in all organisms. tRNA variants that increase mistranslation arise spontaneously and engineered tRNAs can achieve mistranslation frequencies approaching 10% in yeast and bacteria. Interestingly, human genomes contain tRNA variants with the potential to mistranslate. Cells cope with increased mistranslation through multiple mechanisms, though high levels cause proteotoxic stress. The goal of this study was to compare the genetic interactions and the impact on transcriptome and cellular growth of two tRNA variants that mistranslate at a similar frequency but create different amino acid substitutions in Saccharomyces cerevisiae. One tRNA variant inserts alanine at proline codons whereas the other inserts serine for arginine. Both tRNAs decreased growth rate, with the effect being greater for arginine to serine than for proline to alanine. The tRNA that substituted serine for arginine resulted in a heat shock response. In contrast, heat shock response was minimal for proline to alanine substitution. Further demonstrating the significance of the amino acid substitution, transcriptome analysis identified unique up- and down-regulated genes in response to each mistranslating tRNA. Number and extent of negative synthetic genetic interactions also differed depending upon type of mistranslation. Based on the unique responses observed for these mistranslating tRNAs, we predict that the potential of mistranslation to exacerbate diseases caused by proteotoxic stress depends on the tRNA variant. Furthermore, based on their unique transcriptomes and genetic interactions, different naturally occurring mistranslating tRNAs have the potential to negatively influence specific diseases.

| S-EPMC8473984 | biostudies-literature

tRNA senses cellular nutrient status and senescence via amino acid acylation

Project description:We profiled the cellular tRNA charging landscape using next-generation sequencing and identified a subset of tRNA that sense nutrients. The charging levels of tRNAGln were exclusively and significantly decreased in response to amino acid starvation.

2022-11-30 | GSE157510 | GEO

Amino acid analog induces stress response in marine Synechococcus

Project description:In this study, we explored the use of BONCAT in Synechococcus sp. – a globally important cyanobacteria. We characterized the growth and microscopically quantified HPG uptake under a range of HPG concentrations in marine Synechococcus sp. Further, we examined changes in protein expression of Synechococcus sp. grown under normal and nitrate-stressed conditions relative to a non-HPG control.

2021-04-01 | PXD023371 | Pride

Expanded cellular amino acid pools containing phosphoserine, phosphothreonine, and phosphotyrosine.

Project description:Adding nonstandard amino acids to the genetic code of E. coli expands the chemical and biological functional space for proteins. This is accomplished with engineered, orthogonal aminoacyl-tRNA synthetase and tRNA pairs that require a nonstandard amino acid in sufficient intracellular quantities to support protein synthesis. While cotranslational insertion of phosphoserine into proteins has been accomplished, conditions that modulate intracellular phosphoamino acid concentrations are still poorly understood. Here we used genetic and metabolic engineering to increase the free intracellular levels of phosphoserine in E. coli. We show that deletion of the phosphoserine phosphatase serB elevates the intracellular levels of phosphoserine within ranges comparable to those of standard amino acids. These new conditions improved insertion of phosphoserine into recombinant proteins. Surprisingly, we also observed dramatic increases in intracellular levels of phosphothreonine and phosphotyrosine when WT cells were grown in LB with supplemented phosphothreonine and serB deficient cells were grown in low phosphate media with supplemented phosphotyrosine, respectively. These findings remove a major barrier for further expansion of the genetic code with additional phosphorylated amino acids.

| S-EPMC4027946 | biostudies-literature

Inhibition of Rab prenylation by statins induces cellular glycosphingolipid remodeling.

Project description:Statins, which specifically inhibit HMG Co-A reductase, the rate-limiting step of cholesterol biosynthesis, are widely prescribed to reduce serum cholesterol and cardiac risk, but many other effects are seen. We now show an effect of these drugs to induce profound changes in the step-wise synthesis of glycosphingolipids (GSLs) in the Golgi. Glucosylceramide (GlcCer) was increased several-fold in all cell lines tested, demonstrating a widespread effect. Additionally, de novo or elevated lactotriaosylceramide (Lc3Cer; GlcNAc?1-3Gal?1-4GlcCer) synthesis was observed in 70%. Western blot showed that GlcCer synthase (GCS) was elevated by statins, and GCS and Lc3Cer synthase (Lc3S) activities were increased; however, transcript was elevated for Lc3S only. Supplementation with the isoprenoid precursor, geranylgeranyl pyrophosphate (GGPP), a downstream product of HMG Co-A reductase, reversed statin-induced glycosyltransferase and GSL elevation. The Rab geranylgeranyl transferase inhibitor 3-PEHPC, but not specific inhibitors of farnesyl transferase, or geranylgeranyl transferase I, was sufficient to replicate statin-induced GlcCer and Lc3Cer synthesis, supporting a Rab prenylation-dependent mechanism. While total cholesterol was unaffected, the trans-Golgi network (TGN) cholesterol pool was dissipated and medial Golgi GCS partially relocated by statins. GSL-dependent vesicular retrograde transport of Verotoxin and cholera toxin to the Golgi/endoplasmic reticulum were blocked after statin or 3-PEHPC treatment, suggesting aberrant, prenylation-dependent vesicular traffic as a basis of glycosyltransferase increase and GSL remodeling. These in vitro studies indicate a previously unreported link between Rab prenylation and regulation of GCS activity and GlcCer metabolism.

| S-EPMC4691287 | biostudies-literature

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