Inhibition of Glycogen Metabolism Induces Reactive Oxygen Species-Dependent Cytotoxicity in Anaplastic Thyroid Cancer in Female Mice.
Cole D DavidsonJennifer A TomczakEyal AmielFrances E CarrPublished in: Endocrinology (2022)
Anaplastic thyroid cancer (ATC) is one of the most lethal solid tumors, yet there are no effective, long-lasting treatments for ATC patients. Most tumors, including tumors of the endocrine system, exhibit an increased consumption of glucose to fuel cancer progression, and some cancers meet this high glucose requirement by metabolizing glycogen. Our goal was to determine whether ATC cells metabolize glycogen and if this could be exploited for treatment. We detected glycogen synthase and glycogen phosphorylase (PYG) isoforms in normal thyroid and thyroid cancer cell lines and patient-derived biopsy samples. Inhibition of PYG using CP-91,149 induced apoptosis in ATC cells but not normal thyroid cells. CP-91,149 decreased NADPH levels and induced reactive oxygen species accumulation. CP-91,149 severely blunted ATC tumor growth in vivo. Our work establishes glycogen metabolism as a novel metabolic process in thyroid cells, which presents a unique, oncogenic target that could offer an improved clinical outcome.
Keyphrases
- induced apoptosis
- endoplasmic reticulum stress
- reactive oxygen species
- signaling pathway
- oxidative stress
- high glucose
- cell cycle arrest
- endothelial cells
- end stage renal disease
- squamous cell carcinoma
- chronic kidney disease
- type diabetes
- diabetic rats
- metabolic syndrome
- insulin resistance
- cell proliferation
- newly diagnosed
- stress induced
- smoking cessation
- blood pressure
- young adults
- patient reported outcomes
- skeletal muscle
- ultrasound guided
- blood glucose
- replacement therapy
- high fat diet induced