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

Abstract

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 six months. Oncogenic alterations in ATC include aberrant PI3K signaling through receptor tyrosine kinase (RTK) amplification, loss of phosphoinositide phosphatase expression and function, and Akt amplification. Furthermore, the loss of expression of the tumor suppressor thyroid hormone receptor beta (TRβ) is strongly associated with ATC. TRβ is known to suppress PI3K in follicular thyroid cancer and breast cancer by binding to the PI3K regulatory subunit p85⍺. However, the role of TRβ in suppressing PI3K signaling in ATC is not completely delineated. Here we report that TRβ indeed suppresses PI3K signaling in ATC cell lines through unreported genomic mechanisms including a decrease in RTK expression and increase in phosphoinositide and Akt phosphatase expression. Furthermore, the reintroduction and activation of TRβ 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 TRβ but shed light into the implication of TRβ status and activation on inhibitor efficacy in ATC tumors.

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

“…2A ). Endogenous TRβ expression is low in all four ATC cell lines when compared with normal thyroid cells (29). Treatment of each cell line with 10 nM GC-1 for four days yielded a modest but significant decrease in cell growth ( Fig.…”

“…In this study, we tested representative drugs that target the MAPK, PI3K, and cell cycle pathways to assess whether GC-1 could increase their effectiveness. Since we have demonstrated that activation of TRβ in ATC represses the PI3K pathway through genomic mechanisms (2,29), GC-1 with either Buparlisib or Alpelisib would be suppressing PI3K activity in concert. In contrast, TRβ does not directly impact MAPK through transcriptomic modulation so GC-1 in combination with Sorafenib demonstrated concordant effects.…”

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

“…Immunoblots were conducted as described previously 61 . Briefly, proteins were isolated from whole cells in lysis buffer (20mM Tris-HCl (pH 8), 137 mM NaCl, 10% glycerol, 1% Triton X-100, and 2mM EDTA), quantified via Pierce TM BCA Protein Assay Kit (Thermo Fisher Scientific), and 25 µg protein/sample were resolved by polyacrylamide gel electrophoresis and immobilized onto nitrocellulose membranes.…”

“…Immunoblots were conducted as described previously 61 . Briefly, proteins were isolated from whole cells in lysis buffer (20mM Tris-HCl (pH 8), 137 mM NaCl, 10% glycerol, 1%…”

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

“…There were similar findings in colorectal cancer cells in which long-term T 3 exposure resulted in reduced ser473 Akt phosphorylation by an unknown mechanism [ 15 ]. However, as we have recently described, TRβ may play a critical genomic role in PI3K regulation in anaplastic thyroid cancer (ATC) [ 30 ]. While short term (30 min) T 3 exposure failed to reduce pAkt levels, long term exposure (24 h) reduced pAkt and pmTORC1 levels concordantly with changes in gene expression.…”