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Ag120-Mediated Inhibition of ASCT2-Dependent Glutamine Transport has an Anti-Tumor Effect on Colorectal Cancer Cells.

ABSTRACT: Metabolic reprogramming is considered to be a hallmark of cancer, and increased glutamine metabolism plays an important role in the progression of many tumors, including colorectal cancer (CRC). Targeting of glutamine uptake via the transporter protein ASCT2/SLC1A5 (solute carrier family 1 member 5) is considered to be an effective strategy for the treatment of malignant tumors. Here, we demonstrate that Ag120 (ivosidenib), a mutant isocitrate dehydrogenase 1 (IDH1) inhibitor approved for the treatment of certain cancers, acts as an ASCT2 inhibitor in CRC cells. Ag120 blocked glutamine uptake and metabolism, leading to reduced cell proliferation, elevated autophagy, and increased oxidative stress in CRC cells in vitro and in vivo, potentially via the ERK and mTOR signaling pathways. These effects occurred independently of mutant IDH1 activity and were supported by experiments with ASCT2-depleted or -overexpressing cells. These data identify a novel mechanism of Ag120 anti-tumor activity and support further exploration of ASCT2 inhibitors for cancer therapy.

SUBMITTER: Yu W

PROVIDER: S-EPMC8996072 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Ag120-Mediated Inhibition of ASCT2-Dependent Glutamine Transport has an Anti-Tumor Effect on Colorectal Cancer Cells.

Yu Wei W Huang Jianwen J Dong Qichao Q Li Wenting W Jiang Lei L Zhang Qian Q Sun Li L Yuan Shengtao S He Xu X

Frontiers in pharmacology 20220328

Metabolic reprogramming is considered to be a hallmark of cancer, and increased glutamine metabolism plays an important role in the progression of many tumors, including colorectal cancer (CRC). Targeting of glutamine uptake <i>via</i> the transporter protein ASCT2/<i>SLC1A5</i> (solute carrier family 1 member 5) is considered to be an effective strategy for the treatment of malignant tumors. Here, we demonstrate that Ag120 (ivosidenib), a mutant isocitrate dehydrogenase 1 (IDH1) inhibitor appro ...[more]

PMID: 35418865

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Project description:BackgroundColorectal cancer is the second commonly seen cancer around the world and accounts for 13% of all human cancers. Among them, 25% of all case were diagnosed with metastasis and 50% occurs metastasis during the development of disease. Cetuximab is a chimeric monoclonal antibody against epidermal growth factor receptor, and is used for treatment of metastatic colorectal cancer alone or combined with chemotherapy or radiation therapy. Integrin-beta 1 (ITGB1), which is also known as CD29, and plays an important role in development of malignant cancers. However, the effect of ITGB1 in promoting the anti-tumor effect of cetuximab is not fully understand.MethodsThe model of ITGB1 inhibition and overexpression was firstly constructed in LS174T cells, and the viability of cells in each group was detected using CCK-8 assay. The expression of key factors in tumor formation process at transcription level was detected using real-time quantitative polymerase chain reaction method. The expression of key proteins in metastasis process, cell apoptosis and activation of Ras/Raf/MEK signaling pathway was detected using western blotting analysis. And the concentration of key factors of in tumor formation process in cultured medium of LS174T cells were detected using enzyme-linked immunosorbent assay method.ResultsWe found that cetuximab could inhibit the proliferation of LS174T cells, and inhibition of ITGB1 enhanced this effect while overexpression of ITGB1 reduced this effect. We further found that cetuximab could inhibit the expression and secretion of extracellular matrix degradation related molecules in cultured medium and transcription level. Besides, we also found that the expression of key factors in angiogenesis and extracellular matrix degradation related proteins were also reduced after cetuximab treatment. These effects might be mediated by Ras/Raf/MAPK signaling pathway and enhanced after inhibition of ITGB1 expression.ConclusionInhibition of ITGB1 might be a new therapeutic method in colorectal cancer.

Dataset Information

Ag120-Mediated Inhibition of ASCT2-Dependent Glutamine Transport has an Anti-Tumor Effect on Colorectal Cancer Cells.

Publications

Ag120-Mediated Inhibition of ASCT2-Dependent Glutamine Transport has an Anti-Tumor Effect on Colorectal Cancer Cells.

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