Clinical Role of ASCT2 (SLC1A5) in KRAS-Mutated Colorectal Cancer

Toda, Keiichi; Nishikawa, Gen; Iwamoto, Masayoshi; Itatani, Yoshiro; Takahashi, Ryo; Sakai, Yoshiharu; Kawada, Kenji

doi:10.3390/ijms18081632

Cited by 63 publications

(56 citation statements)

References 33 publications

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“…Similar to the situation in MYC-driven cancer cells, glutamine uptake is enhanced in K-Ras-driven cells via upregulation of SLC1A5 181 . Additionally, K-Ras-driven cells are characterized by increased expression of GOT1 and GOT2 182,183 .…”

Section: Crosstalk Between Glutamine Metabolism and Oncogenic Signalingmentioning

confidence: 67%

Glutamine reliance in cell metabolism

et al. 2020

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As knowledge of cell metabolism has advanced, glutamine has been considered an important amino acid that supplies carbon and nitrogen to fuel biosynthesis. A recent study provided a new perspective on mitochondrial glutamine metabolism, offering mechanistic insights into metabolic adaptation during tumor hypoxia, the emergence of drug resistance, and glutaminolysis-induced metabolic reprogramming and presenting metabolic strategies to target glutamine metabolism in cancer cells. In this review, we introduce the various biosynthetic and bioenergetic roles of glutamine based on the compartmentalization of glutamine metabolism to explain why cells exhibit metabolic reliance on glutamine. Additionally, we examined whether glutamine derivatives contribute to epigenetic regulation associated with tumorigenesis. In addition, in discussing glutamine transporters, we propose a metabolic target for therapeutic intervention in cancer.

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Section: Crosstalk Between Glutamine Metabolism and Oncogenic Signalingmentioning

confidence: 67%

Glutamine reliance in cell metabolism

et al. 2020

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“…3A). Indeed, previous immunohistochemistry (IHC) studies found that both SLC1A5 and SLC7A5 were up-regulated in colon cancer cells (Huang et al 2014;Wang et al 2016;Toda et al 2017).…”

Section: Myc Promotes the Expression Of Trp Transporters And Enzymes mentioning

confidence: 99%

MYC promotes tryptophan uptake and metabolism by the kynurenine pathway in colon cancer

et al. 2019

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Tumors display increased uptake and processing of nutrients to fulfill the demands of rapidly proliferating cancer cells. Seminal studies have shown that the proto-oncogene MYC promotes metabolic reprogramming by altering glutamine uptake and metabolism in cancer cells. How MYC regulates the metabolism of other amino acids in cancer is not fully understood. Using high-performance liquid chromatography (HPLC)-tandem mass spectrometry (LC-MS/MS), we found that MYC increased intracellular levels of tryptophan and tryptophan metabolites in the kynurenine pathway. MYC induced the expression of the tryptophan transporters SLC7A5 and SLC1A5 and the enzyme arylformamidase (AFMID), involved in the conversion of tryptophan into kynurenine. SLC7A5, SLC1A5, and AFMID were elevated in colon cancer cells and tissues, and kynurenine was significantly greater in tumor samples than in the respective adjacent normal tissue from patients with colon cancer. Compared with normal human colonic epithelial cells, colon cancer cells were more sensitive to the depletion of tryptophan. Blocking enzymes in the kynurenine pathway caused preferential death of established colon cancer cells and transformed colonic organoids. We found that only kynurenine and no other tryptophan metabolite promotes the nuclear translocation of the transcription factor aryl hydrocarbon receptor (AHR). Blocking the interaction between AHR and kynurenine with CH223191 reduced the proliferation of colon cancer cells. Therefore, we propose that limiting cellular kynurenine or its downstream targets could present a new strategy to reduce the proliferation of MYC-dependent cancer cells.

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“…9,37,38 Furthermore, glutamine is the major carbon source for the tricarboxylic acid cycle when RAS is activated. 38 SLC1A5 is upregulated through KRAS signaling in colorectal cancer, 39 and the conversion of glutamine to glutamate by GLS is modulated by RAS. 38 This is in agreement with our findings that KRAS mutated tumors show a trend toward a higher SLC1A5 mRNA expression and a significantly higher GLS mRNA expression.…”

Section: Nsclc Tumor Cell Metabolism In Relation To Histological Subtmentioning

confidence: 99%

Glucose and glutamine metabolism in relation to mutational status in NSCLC histological subtypes

et al. 2019

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BackgroundBoth hypoxia and oncogenic mutations rewire tumor metabolism. In this study, glucose and glutamine metabolism‐related markers were examined in stage I ‐ resectable stage IIIA non‐small cell lung cancer (NSCLC). Furthermore, expression of metabolism‐related markers was correlated with mutational status to examine mutations associated with rewired tumor metabolism.MethodsMutation analysis was performed for 97 tumors. Glucose and glutamine metabolism‐related marker expression was measured by immunofluorescent staining (protein) and qPCR (mRNA) (n = 81).ResultsGlutamine metabolism‐related markers were significantly higher in adeno‐ than squamous cell NSCLCs. Glucose transporter 1 (GLUT1) protein expression was higher in solid compared to lepidic adenocarcinomas (P < 0.01). In adenocarcinomas, mRNA expression of glutamine transporter SLC1A5 correlated with tumor size (r(p) = 0.41, P = 0.005). Furthermore, SLC1A5 protein expression was significantly higher in adenocarcinomas with worse pTNM stage (r(s) = 0.39, P = 0.009). EGFR‐mutated tumors showed lower GLUT1 protein (P = 0.017), higher glutaminase 2 (GLS2) protein (P = 0.025) and higher GLS2 mRNA expression (P = 0.004), compared to EGFR wild‐type tumors. GLS mRNA expression was higher in KRAS‐mutated tumors (P = 0.019). TP53‐mutated tumors showed higher GLUT1 expression (P = 0.009).ConclusionsNSCLC is a heterogeneous disease, with differences in mutational status and metabolism‐related marker expression between adeno‐ and squamous cell NSCLCs, and also within adenocarcinoma subtypes. GLUT1 and SLC1A5 expression correlate with aggressive tumor behavior in adenocarcinomas but not in squamous cell NSCLCs. Therefore, these markers could steer treatment modification for subgroups of adenocarcinoma patients. TP53, EGFR and KRAS mutations are associated with expression of glucose and glutamine metabolism‐related markers in NSCLC.

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Clinical Role of ASCT2 (SLC1A5) in KRAS-Mutated Colorectal Cancer

Cited by 63 publications

References 33 publications

Glutamine reliance in cell metabolism

Glutamine reliance in cell metabolism

MYC promotes tryptophan uptake and metabolism by the kynurenine pathway in colon cancer

Glucose and glutamine metabolism in relation to mutational status in NSCLC histological subtypes

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