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Targeting glutamine metabolism exhibits anti-tumor effects in thyroid cancer
1Department of Nuclear Medicine, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 600 Yishan Road, Shanghai, 200233, People's Republic of China.
Background:
Effective treatment for patients with advanced thyroid cancer is lacking. Metabolism reprogramming is required for cancer to undergo oncogenic transformation and rapid tumorigenic growth. Glutamine is frequently used by cancer cells for active bioenergetic and biosynthetic needs. This study aims to investigate whether targeting glutamine metabolism is a promising therapeutic strategy for thyroid cancer.
Methods:
The expression of glutaminase (GLS) and glutamate dehydrogenase (GDH) in thyroid cancer tissues was evaluated by immunohistochemistry, and glutamine metabolism-related genes were assessed using real time-qPCR and western blotting. The effects of glutamine metabolism inhibitor 6-diazo-5-oxo-l-norleucine (DON) on thyroid cancer cells were determined by CCK-8, clone formation assay, Edu incorporation assay, flow cytometry, and Transwell assay. The mechanistic study was performed by real time-qPCR, western blotting, Seahorse assay, and gas chromatography-mass spectrometer assay. The effect of DON prodrug (JHU-083) on thyroid cancer in vivo was assessed using xenograft tumor models in BALB/c nude mice.
Results:
GLS and GDH were over-expressed in thyroid cancer tissues, and GLS expression was positively associated with lymph-node metastasis and TNM stage. The growth of thyroid cancer cells was significantly inhibited when cultured in glutamine-free medium. Targeting glutamine metabolism with DON inhibited the proliferation of thyroid cancer cells. DON treatment did not promote apoptosis, but increased the proportion of cells in the S phase, accompanied by the decreased expression of cyclin-dependent kinase 2 and cyclin A. DON treatment also significantly inhibited the migration and invasion of thyroid cancer cells by reducing the expression of N-cadherin, Vimentin, matrix metalloproteinase-2, and matrix metalloproteinase-9. Non-essential amino acids, including proline, alanine, aspartate, asparagine, and glycine, were reduced in thyroid cancer cells treated with DON, which could explain the decrease of proteins involved in migration, invasion, and cell cycle. The efficacy and safety of DON prodrug (JHU-083) for thyroid cancer treatment were verified in a mouse model. In addition to suppressing the proliferation and metastasis potential of thyroid cancer in vivo, enhanced innate immune response was also observed in JHU-083-treated xenograft tumors as a result of decreased expression of cluster of differentiation 47 and programmed cell death ligand 1.
Conclusions:
Thyroid cancer exhibited enhanced glutamine metabolism, as evidenced by the glutamine dependence of thyroid cancer cells and high expression of multiple glutamine metabolism-related genes. Targeting glutamine metabolism with DON prodrug could be a promising therapeutic option for advanced thyroid cancer.
Insights
Targeting glutamine metabolism with DON prodrug shows promise for advanced thyroid cancer. This approach inhibits cancer cell proliferation and metastasis while potentially enhancing immune response.
Area of Science:
- Oncology
- Cancer Metabolism
Background:
- Advanced thyroid cancer lacks effective treatments.
- Cancer cells reprogram metabolism, utilizing glutamine for energy and biosynthesis.
- Targeting glutamine metabolism is explored as a therapeutic strategy.
Purpose of the Study:
- Investigate the role of glutamine metabolism in thyroid cancer.
- Evaluate the therapeutic potential of targeting glutamine metabolism in thyroid cancer.
Main Methods:
- Assessed glutaminase (GLS) and glutamate dehydrogenase (GDH) expression in thyroid cancer tissues.
- Utilized the glutamine metabolism inhibitor 6-diazo-5-oxo-l-norleucine (DON) and its prodrug JHU-083 in cell lines and xenograft models.
- Analyzed cellular proliferation, cell cycle, migration, invasion, and gene expression.
Main Results:
- GLS and GDH were overexpressed in thyroid cancer, correlating with metastasis and stage.
- DON inhibited thyroid cancer cell proliferation, migration, and invasion.
- DON treatment altered cell cycle progression and reduced key proteins involved in metastasis.
- JHU-083 suppressed tumor growth and metastasis in vivo, also enhancing innate immune response by downregulating CD47 and PD-L1.
Conclusions:
- Thyroid cancer cells exhibit high glutamine metabolism and dependence.
- Targeting glutamine metabolism with DON prodrug (JHU-083) is a promising therapeutic strategy for advanced thyroid cancer.
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