Thyroid Hormone Receptor β Suppresses Cancer Cell Activity by Differential Regulation of Glycogen Metabolism

Anaplastic thyroid cancer (ATC) is one of the most lethal endocrine cancers with no enduring therapies. Thyroid hormone receptor β (TRβ), a recognized tumor suppressor, modulates the transcriptome altering gene expression in numerous intracellular signaling pathways. Our recent studies revealed that TRβ agonism inhibits glycogen metabolism in ATC cells. Our goal in the present study was to delineate the molecular mechanisms by which TRβ regulates glycogen synthesis and breakdown. In ATC cells, activation of TRβ induced changes in expression of genes and proteins in glycogen signaling concordant with downregulation of cancer metabolism. The impact on the cancer cell metabolic phenotype was determined by glycogen levels, cell viability, and reactive oxygen species characterization. Our results revealed that TRβ activation differentially regulates glycogen signaling pathways reflective of the genetic landscape of the cells. This suggests TRβ can suppress tumor growth and progression through multiple steps in glycogen metabolism, giving it a unique and distinct role in fine-tuning the microenvironment of the cell as an internal sensor of the general environment of the cell. These studies reveal the potential of a synergistic effect of TRβ agonism and inhibition of glycogen metabolism in the treatment of aggressive dedifferentiated thyroid cancers.