Thyroid Hormone Receptors and their Role in Cell Proliferation and Cancer

Martínez-Iglesias, Olaia; Ruíz-Llorente, Lidia; Jurado, Constanza Contreras; Aranda, Ana

doi:10.1016/b978-0-12-819801-8.00011-9

Cited by 2 publications

(2 citation statements)

References 55 publications

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“…Proteins were isolated from whole cells in lysis buffer and visualized by Western blot as previously described (9, 10, 18). Specific proteins were detected with the indicated antibodies (Table 1); immunoreactive proteins were detected by enhanced chemiluminescence (Thermo Fisher Scientific) on a ChemiDoc XRS+ (Bio-Rad Laboratories).…”

Section: Methodsmentioning

confidence: 99%

“…There is compelling evidence that the nuclear receptor thyroid hormone receptor beta (TRβ) is a suppressor of tumor progression, invasion, and metastases in multiple solid tumors including thyroid, breast, colon and other cancers(1). Cell-based and animal studies reveal that liganded TRβ induces apoptosis, reduces an aggressive phenotype, decreases cancer stem cell populations, and slows tumor growth through modulation of a complex transcriptional network (2–9). Transcriptional regulation by TRβ is critical for its function as a tumor suppressor because it acts as both a signal transducer and facilitator of long-term epigenetic programming for maintenance of cell identity.…”

Section: Introductionmentioning

confidence: 99%

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TRβ Agonism Induces Tumor Suppression and Enhances Drug Efficacy in Anaplastic Thyroid Cancer in Female Mice

Gillis

Davidson

et al. 2021

Preprint

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Background: Anaplastic thyroid cancer (ATC) is one of the most lethal endocrine cancers, with an average survival time of six months after diagnosis. These aggressive tumors have very limited treatment options highlighting a need for a deeper understanding of its mechanisms for development of more effective therapies. We have previously shown that the liganded thyroid hormone receptor beta (TRβ) can function as a tumor suppressor and induce re-differentiation in ATC cells. We therefore tested the hypothesis that selective activation of TRβ with sobetirome (GC-1) could reduce the tumorigenic phenotypes of ATC cell lines and improve the efficacy of clinically relevant therapeutics. Methods: We used a panel of four ATC cell lines with variable genetic backgrounds to assess the ability of GC-1 to reduce the aggressive phenotype. The effects of GC-1 alone or in combination with buparlisib, alpelisib, sorafenib, and palbociclib on cell growth, viability, and migration were determined and compared with the gene expression levels of selected markers. The impact of these treatments on the cancer stem cell population was assessed by tumorsphere assay. Thyroid differentiation markers were measured by gene analysis, and sodium iodide symporter (NIS) protein level and function were determined. Results: Our results show that GC-1 alone can decrease cell viability, growth, and slow cell migration in all four ATC cell lines. In addition, GC-1 is able to further block each of these phenotypes when combined with buparlisib, alpelisib, sorafenib, or palbociclib. GC-1 alone blocks thyrosphere outgrowth in all cell lines and increases the efficacy of each of the therapeutic agents tested. GC-1 increased NIS transcript and protein levels to allow for increased iodide uptake in ATC cells. Conclusion: Activation of TRβ with selective agonist sobetirome (GC-1) reduces the aggressive phenotype and induced re-differentiation in ATC cells and increases the efficacy of therapeutic agents that are currently used in the treatment of ATC. These results indicate that selective activation of TRβ not only induces a tumor suppression program de novo but enhances the effectiveness of anti-cancer agents.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

TRβ Agonism Induces Tumor Suppression and Enhances Drug Efficacy in Anaplastic Thyroid Cancer in Female Mice

Gillis

Davidson

et al. 2021

Preprint

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TRβ Agonism Induces Tumor Suppression and Enhances Drug Efficacy in Anaplastic Thyroid Cancer in Female Mice

Gillis,

Cozzens,

Wilson

et al. 2023

Endocrinology

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Thyroid hormone receptor beta (TRβ) is a recognized tumor suppressor in numerous solid cancers. The molecular signaling of TRβ has been elucidated in several cancer types through re-expression models. Remarkably, the potential impact of selective activation of endogenous TRβ on tumor progression remains largely unexplored. We used cell-based and in vivo assays to evaluate the effects of the TRβ 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 redifferentiation of the ATC cell lines with different mutational backgrounds. Of note, this selective activation of TRβ 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 TRβ not only induces a tumor suppression program de novo but enhances the effectiveness of anticancer agents, revealing potential novel combination therapies for ATC and other aggressive solid tumors.

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Thyroid Hormone Receptors and their Role in Cell Proliferation and Cancer

Cited by 2 publications

References 55 publications

TRβ Agonism Induces Tumor Suppression and Enhances Drug Efficacy in Anaplastic Thyroid Cancer in Female Mice

TRβ Agonism Induces Tumor Suppression and Enhances Drug Efficacy in Anaplastic Thyroid Cancer in Female Mice

TRβ Agonism Induces Tumor Suppression and Enhances Drug Efficacy in Anaplastic Thyroid Cancer in Female Mice

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