Inhibition of Glycogen Metabolism Induces Reactive Oxygen Species-Dependent Cytotoxicity in Anaplastic Thyroid Cancer in Female Mice

Davidson, Cole D.; Tomczak, Jennifer A.; Amiel, Eyal; Carr, Frances E.

doi:10.1210/endocr/bqac169

Cited by 6 publications

(3 citation statements)

References 60 publications

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“…Further research is needed to understand certain elements of the relationship between the regulation of glycogen degradation and the hepatocellular intraluminal redox state. In addition, glycogen metabolism has recently become one of the targets of antitumor therapy [ 53 ]. One explanation for this is the relationship between glycogen metabolism and redox homeostasis.…”

Section: Discussionmentioning

confidence: 99%

Glycogen—Endoplasmic Reticulum Connection in the Liver

Mandl

2023

IJMS

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Glycogen, the branched polymer of glucose is found mainly in the liver and muscle in mammals. Along with several other proteins, glycogen forms separate cellular organelles, and particles in cells. Glycogen particles in the liver have a special metabolic and also regulatory connection to the intracellular endomembrane system, particularly the endoplasmic reticulum. This connection is part of the organelle homeostasis in hepatocytes and forms a “glycogenoreticular system”. The actual size of hepatic glycogen stores and the rate of glycogenolysis determines several essential liver-specific metabolic processes, such as glucose secretion for the maintenance of blood glucose levels or the glucuronidation of certain vital endo-, and xenobiotics, and are also related to liver antioxidant defense. In starvation, and in certain physiological and pathological states, where glycogen stores are depleted, functions of the glycogenoreticular system are altered. The starvation-induced depletion of hepatic glycogen content changes the biotransformation of various endo- and xenobiotics. This can be observed especially in acute DILI (drug-induced liver injury) due to paracetamol overdose, which is the most common cause of acute liver failure in the West.

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Section: Discussionmentioning

confidence: 99%

Glycogen—Endoplasmic Reticulum Connection in the Liver

Mandl

2023

IJMS

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“…Several clinical studies have reported monotherapy with a multi-tyrosine kinase inhibitor is not recommended for mild effects in patients with ATC [ 66 , 67 ]. Recently, many investigations have shown combination treatment with these drugs is more effective than drug monotherapy for ATC [ 68 – 71 ]. We also showed co-inhibition of glutamine and one-carbon metabolism increased the efficacy of lenvatinib and sorafenib.…”

Section: Discussionmentioning

confidence: 99%

Co-inhibition of glutaminolysis and one-carbon metabolism promotes ROS accumulation leading to enhancement of chemotherapeutic efficacy in anaplastic thyroid cancer

Hwang,

Yun,

Jeong

et al. 2023

Cell Death Dis

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Anaplastic thyroid cancer (ATC) is one of the most aggressive tumors with an extremely poor prognosis. Based on the several biological features related to glutamine metabolism in ATC, we hypothesized glutaminolysis inhibition induces cell death in ATC cells. However, glutamine metabolism inhibition triggered cell growth arrest independent of cell death in ATC, suggesting that other signaling pathways avoid glutamine metabolism inhibition-induced stress exist. To investigate the functional mechanism against glutamine metabolism inhibition, we conducted mRNA and ATAC-Sequencing data analysis and found that glutamine deprivation increased ATF4-mediated one-carbon metabolism. When we inhibited PHGDH, the first rate-limiting enzyme for one-carbon metabolism, cell growth arrest was promoted upon glutamine metabolism inhibition by accumulating intracellular ROS. We next observed that the co-inhibition of glutamine and one-carbon metabolism could augment the anticancer effects of drugs used in patients with ATC. Finally, single-cell RNA sequencing analysis revealed that one-carbon metabolism was strengthened through the evolutionary process from PTC to ATC. Collectively, our data demonstrate that one-carbon metabolism has a potential role of modulation of cell fate in metabolic stress and can be a therapeutic target for enhancing antitumor effects in ATC.

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“…For example, kinase inhibitors dasatinib and trametinib were shown to alter metabolic flux in anaplastic and papillary thyroid cancer cells [ 45 ]. In anaplastic thyroid cells in mice, targeting glycogen metabolism by inhibiting glycogen phosphorylase resulted in increased glucose flux, impairment of PPP, reactive oxygen species accumulation, and eventual cytotoxicity [ 46 ].…”

Section: Metabolism In Thyroid and Other Cancersmentioning

confidence: 99%

Toward Systems-Level Metabolic Analysis in Endocrine Disorders and Cancer

Lakhani,

Kang,

Kang

et al. 2023

Endocrinol Metab

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Metabolism is a dynamic network of biochemical reactions that support systemic homeostasis amidst changing nutritional, environmental, and physical activity factors. The circulatory system facilitates metabolite exchange among organs, while the endocrine system finely tunes metabolism through hormone release. Endocrine disorders like obesity, diabetes, and Cushing’s syndrome disrupt this balance, contributing to systemic inflammation and global health burdens. They accompany metabolic changes on multiple levels from molecular interactions to individual organs to the whole body. Understanding how metabolic fluxes relate to endocrine disorders illuminates the underlying dysregulation. Cancer is increasingly considered a systemic disorder because it not only affects cells in localized tumors but also the whole body, especially in metastasis. In tumorigenesis, cancer-specific mutations and nutrient availability in the tumor microenvironment reprogram cellular metabolism to meet increased energy and biosynthesis needs. Cancer cachexia results in metabolic changes to other organs like muscle, adipose tissue, and liver. This review explores the interplay between the endocrine system and systems-level metabolism in health and disease. We highlight metabolic fluxes in conditions like obesity, diabetes, Cushing’s syndrome, and cancers. Recent advances in metabolomics, fluxomics, and systems biology promise new insights into dynamic metabolism, offering potential biomarkers, therapeutic targets, and personalized medicine.

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Inhibition of Glycogen Metabolism Induces Reactive Oxygen Species-Dependent Cytotoxicity in Anaplastic Thyroid Cancer in Female Mice

Cited by 6 publications

References 60 publications

Glycogen—Endoplasmic Reticulum Connection in the Liver

Glycogen—Endoplasmic Reticulum Connection in the Liver

Co-inhibition of glutaminolysis and one-carbon metabolism promotes ROS accumulation leading to enhancement of chemotherapeutic efficacy in anaplastic thyroid cancer

Toward Systems-Level Metabolic Analysis in Endocrine Disorders and Cancer

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