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

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.

Common tumor-suppressive signaling of thyroid hormone receptor beta in breast and thyroid cancer cells.

The thyroid hormone receptor beta (TRß) is a tumor suppressor in multiple types of solid tumors, most prominently in breast and thyroid cancer. An increased understanding of the molecular mechanisms by which TRß abrogates tumorigenesis will aid in understanding the core tumor-suppressive functions of TRß. Here, we restored TRß expression in the MDA-MB-468 basal-like breast cancer cell line and perform RNA-sequencing to determine the TRß-mediated changes in gene expression and associated signaling pathways. The TRß expressing MDA-MB-468 cells exhibit a more epithelial character as determined by principle component analysis-based iterative PAM50 subtyping score and through reduced expression of mesenchymal cytokeratins. The epithelial to mesenchymal transition pathway is also significantly reduced. The MDA-MB-468 data set was further compared with RNA sequencing results from TRß expressing thyroid cancer cell line SW1736 to determine which genes are TRß correspondingly regulated across both cell types. Several pathways including lipid metabolism and chromatin remodeling processes were observed to be altered in the shared gene set. These data provide novel insights into the molecular mechanisms by which TRß suppresses breast tumorigenesis.

Thyroid Hormone Receptor Beta as Tumor Suppressor: Untapped Potential in Treatment and Diagnostics in Solid Tumors.

There is compelling evidence that the nuclear receptor TRß, a member of the thyroid hormone receptor (TR) family, is a tumor suppressor in thyroid, breast, and other solid tumors. Cell-based and animal studies reveal that the liganded TRß induces apoptosis, reduces an aggressive phenotype, decreases stem cell populations, and slows tumor growth through modulation of a complex interplay of transcriptional networks. TRß-driven tumor suppressive transcriptomic signatures include repression of known drivers of proliferation such as PI3K/Akt pathway, activation of novel signaling such as JAK1/STAT1, and metabolic reprogramming in both thyroid and breast cancers. The presence of TRß is also correlated with a positive prognosis and response to therapeutics in BRCA+ and triple-negative breast cancers, respectively. Ligand activation of TRß enhances sensitivity to chemotherapeutics. TRß co-regulators and bromodomain-containing chromatin remodeling proteins are emergent therapeutic targets. This review considers TRß as a potential biomolecular diagnostic and therapeutic target.

Thyroid Hormone Receptor Beta Inhibits PI3K-Akt-mTOR Signaling Axis in Anaplastic Thyroid Cancer via Genomic Mechanisms.

Thyroid cancer is the most common endocrine malignancy, and the global incidence has increased rapidly over the past few decades. Anaplastic thyroid cancer (ATC) is highly aggressive, dedifferentiated, and patients have a median survival of fewer than 6 months. Oncogenic alterations in ATC include aberrant phosphoinositide 3 kinase (PI3K) signaling through receptor tyrosine kinase (RTK) amplification, loss of phosphoinositide phosphatase expression and function, and protein kinase B (Akt) amplification. Furthermore, the loss of expression of the tumor suppressor thyroid hormone receptor beta (TRß) is strongly associated with ATC. TRß is known to suppress PI3K in follicular thyroid cancer and breast cancer by binding to the PI3K regulatory subunit p85α. However, the role of TRß in suppressing PI3K signaling in ATC is not completely delineated. Here we report that TRß indeed suppresses PI3K signaling in ATC cell lines through unreported genomic mechanisms, including a decrease in RTK expression and an increase in phosphoinositide and Akt phosphatase expression. Furthermore, the reintroduction and activation of TRß in ATC cell lines enables an increase in the efficacy of the competitive PI3K inhibitors LY294002 and buparlisib on cell viability, migration, and suppression of PI3K signaling. These findings not only uncover additional tumor suppressor mechanisms of TRß but shed light on the implication of TRß status and activation on inhibitor efficacy in ATC tumors.

Thyroid Hormone Receptor Beta Induces a Tumor-Suppressive Program in Anaplastic Thyroid Cancer.

The thyroid hormone receptor beta (TRß), a key regulator of cellular growth and differentiation, is frequently dysregulated in cancers. Diminished expression of TRß is noted in thyroid, breast, and other solid tumors and is correlated with more aggressive disease. Restoration of TRß levels decreased tumor growth supporting the concept that TRß could function as a tumor suppressor. Yet, the TRß tumor suppression transcriptome is not well delineated and the impact of TRß is unknown in aggressive anaplastic thyroid cancer (ATC). Here, we establish that restoration of TRß expression in the human ATC cell line SW1736 (SW-TRß) reduces the aggressive phenotype, decreases cancer stem cell populations and induces cell death in a T3-dependent manner. Transcriptomic analysis of SW-TRß cells via RNA sequencing revealed distinctive expression patterns induced by ligand-bound TRß and revealed novel molecular signaling pathways. Of note, liganded TRß repressed multiple nodes in the PI3K/AKT pathway, induced expression of thyroid differentiation markers, and promoted proapoptotic pathways. Our results further revealed the JAK1-STAT1 pathway as a novel, T3-mediated, antitumorigenic pathway that can be activated in additional ATC lines. These findings elucidate a TRß-driven tumor suppression transcriptomic signature, highlight unexplored therapeutic options for ATC, and support TRß activation as a promising therapeutic option in cancers. IMPLICATIONS: TRß-T3 induced a less aggressive phenotype and tumor suppression program in anaplastic thyroid cancer cells revealing new potential therapeutic targets.