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 p85α. 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 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 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.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
Cole D. Davidson: Conceptualization, Formal analysis, Investigation, Writing – Original draft preparation, Visualization. Eric L. Bolf:Conceptualization, Formal analysis, Investigation, Writing – Review & editing. Noelle E. Gillis: Formal analysis, Investigation, Writing – Review & editing. Lauren M. Cozzens:Formal analysis, Investigation. Jennifer A. Tomczak:Investigation, Writing – Review & editing. Frances E. Carr:Resources, Writing – Review & editing, Supervision, Project administration, Funding acquisition.
The research reported here was supported by grants from National Institutes of Health U54 GM115516 for the Northern New England Clinical and Translational Research Network; National Cancer Institute 1F99CA245796-01; UVM Cancer Center-Lake Champlain Cancer Research Organization (C3) 12577-21; and UVM Larner College of Medicine.
No potential conflicts of interest were disclosed.
Abbreviations
- Akt
- protein kinase B;
- ATC
- anaplastic thyroid cancer;
- AXL
- tyrosine-protein kinase receptor UFO;
- EGFR
- epidermal growth factor receptor;
- ELISA
- enzyme-linked immunosorbent assay;
- FGFR3/4/L1
- fibroblast growth factor receptor 3/4/like 1;
- FTC
- follicular thyroid cancer;
- GSK3β
- glycogen synthase kinase 3 beta;
- GYS1
- glycogen synthase 1;
- HER2
- receptor tyrosine-protein kinase erbB-2;
- HER3
- receptor tyrosine-protein kinase erbB-3;
- INPP4B
- inositol polyphosphate 4-phosphatase type II;
- INPP5J
- phosphatidylinositol 4,5-bisphosphate 5-phosphatase A;
- JAK1
- janus kinase 1;
- mTORC1/2
- mammalian target of rapamycin complex 1/2;
- p70S6K
- ribosomal protein S6 kinase beta-1 PDPK1, 3-phosphoinositide dependent protein kinase 1;
- PDTC
- poorly differentiated thyroid cancer;
- PEKHA2
- tandem-PH-domain-containing protein-2;
- PHLPP1
- PH domain and leucine-rich repeat-protein phosphatase 1;
- PI(3,4)P2
- phosphatidylinositol 3,4-bisphosphate;
- PI(3)P
- phosphatidylinositol 3-phosphate;
- PI(4,5)P2
- phosphatidylinositol 4,5-bisphosphate;
- PI3K
- phosphoinositide 3 kinase;
- PIP3
- phosphatidylinositol 3,4,5 trisphosphate;
- PPP2R5B
- protein phosphatase 2R5B;
- PTC
- papillary thyroid cancer;
- PTEN
- phosphatase and tensin homolog;
- PTPN13
- protein-tyrosine-phosphatase-like protein-1;
- ROR1
- neurotrophic tyrosine kinase receptor-related 1;
- RT-qPCR
- reverse transcriptase quantitative polymerase chain reaction;
- RTK
- receptor tyrosine kinase;
- RUNX2
- runt-related transcription factor 2;
- STAT1
- signal transducer and activator of transcription 1;
- T3
- triiodothyronine;
- TRβ
- thyroid hormone receptor beta