Biology subjects

Carr, F. E.

Publications and source records attributed to Carr, F. E..

3 recordsLinked to original sources

bioRxiv2022

Inhibition of Glycogen Metabolism Induces Reactive Oxygen Species-Dependent Apoptosis in Anaplastic Thyroid Cancer

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 if 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 that presents a unique, oncogenic target that could offer an improved clinical outcome. SignificanceGlycogen metabolism plays an important role in combating reactive oxygen species and apoptosis in anaplastic thyroid cancer. Glycogen phosphorylase was inhibited with small molecule inhibitors that limited cell proliferation in vitro and blunted tumor growth in a nude mouse xenograft. This study demonstrates that glycogen metabolism is a viable target in one of the most lethal solid tumors.

cancer biology↗

bioRxiv2021

A Thyroid Hormone Receptor Beta Specific Agonist Suppresses Anaplastic Thyroid Cancer Cell Phenotype and Increases Efficacy of Therapeutic Agents

Thyroid hormone receptor beta (TR{beta}) is a recognized tumor suppressor in numerous solid cancers. The molecular signaling of TR{beta} has been elucidated in several cancer types through re-expression models. Remarkably, the potential impact of selective activation of endogenous TR{beta} on tumor progression remains largely unexplored. We used cell-based and in vivo assays to evaluate the effects of the TR{beta} agonist Sobetirome (GC-1) on a particularly aggressive and dedifferentiated cancer, anaplastic thyroid cancer (ATC). Here we report that GC-1 reduced the tumorigenic phenotype, decreased cancer stem-like cell populations, and induced re-differentiation of the ATC cell lines with different mutational backgrounds. Of note, this selective activation of TR{beta} amplified the effects of therapeutic agents in blunting the aggressive cell phenotype and stem-cell growth. In xenograft assays, GC-1 alone inhibited tumor growth and was as effective as the kinase inhibitor, Sorafenib. These results indicate that selective activation of TR{beta} not only induces a tumor suppression program de novo but enhances the effectiveness of anti-cancer agents revealing potential novel combination therapies for ATC and other aggressive solid tumors.

cancer biology↗

bioRxiv2021

Thyroid Hormone Dependent Transcriptional Programming by TRβ Requires SWI/SNF Chromatin Remodelers

Transcriptional regulation in response to thyroid hormone (T3) is a dynamic and cell-type specific process that maintains cellular homeostasis and identity in all tissues. However, our understanding of the mechanisms of thyroid hormone receptor (TR) actions at the molecular level are actively being refined. We used an integrated genomics approach to profile and characterize the cistrome of TR{beta}, map changes in chromatin accessibility, and capture the transcriptomic changes in response to T3 in normal thyroid cells. There are significant shifts in TR{beta} genomic occupancy in response to T3, which are associated with differential chromatin accessibility, and differential recruitment of SWI/SNF chromatin remodelers. We further demonstrate selective recruitment of BAF and PBAF SWI/SNF complexes to TR{beta} binding sites, revealing novel differential functions in regulating chromatin accessibility and gene expression. Our findings highlight three distinct modes of TR{beta} interaction with chromatin and coordination of coregulator activity.

genomics↗