Triiodothyronine regulates cell growth and survival in renal cell cancer

Czarnecka,Anna  M.; Matak,Damian; Szymanski,Lukasz; Czarnecka,Karolina   H.; Lewicki,Slawomir; Zdanowski,Robert; Brzezianska-Lasota,Ewa; Szczylik,Cezary

doi:10.3892/ijo.2016.3668

Triiodothyronine regulates cell growth and survival in renal cell cancer

Authors:
- Anna M. Czarnecka
- Damian Matak
- Lukasz Szymanski
- Karolina H. Czarnecka
- Slawomir Lewicki
- Robert Zdanowski
- Ewa Brzezianska-Lasota
- Cezary Szczylik
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Affiliations: Department of Oncology with Laboratory of Molecular Oncology, Military Institute of Medicine, Warsaw, Poland, Department of Molecular Bases of Medicine, Medical University of Lodz, Lodz, Poland, Department of Regenerative Medicine, Military Institute of Hygiene and Epidemiology, Warsaw, Poland
Published online on: August 23, 2016 https://doi.org/10.3892/ijo.2016.3668
Pages: 1666-1678

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Abstract

Triiodothyronine plays an important role in the regulation of kidney cell growth, differentiation and metabolism. Patients with renal cell cancer who develop hypothyreosis during tyrosine kinase inhibitor (TKI) treatment have statistically longer survival. In this study, we developed cell based model of triiodothyronine (T3) analysis in RCC and we show the different effects of T3 on renal cell cancer (RCC) cell growth response and expression of the thyroid hormone receptor in human renal cell cancer cell lines from primary and metastatic tumors along with human kidney cancer stem cells. Wild-type thyroid hormone receptor is ubiquitously expressed in human renal cancer cell lines, but normalized against healthy renal proximal tube cell expression its level is upregulated in Caki-2, RCC6, SKRC-42, SKRC-45 cell lines. On the contrary the mRNA level in the 769-P, ACHN, HKCSC, and HEK293 cells is significantly decreased. The TRβ protein was abundant in the cytoplasm of the 786-O, Caki-2, RCC6, and SKRC-45 cells and in the nucleus of SKRC-42, ACHN, 769-P and cancer stem cells. T3 has promoting effect on the cell proliferation of HKCSC, Caki-2, ASE, ACHN, SK-RC-42, SMKT-R2, Caki-1, 786-0, and SK-RC-45 cells. Tyrosine kinase inhibitor, sunitinib, directly inhibits proliferation of RCC cells, while thyroid hormone receptor antagonist 1-850 (CAS 251310‑57-3) has less significant inhibitory impact. T3 stimulation does not abrogate inhibitory effect of sunitinib. Renal cancer tumor cells hypostimulated with T3 may be more responsive to tyrosine kinase inhibition. Moreover, some tumors may be considered as T3-independent and present aggressive phenotype with thyroid hormone receptor activated independently from the ligand. On the contrary proliferation induced by deregulated VHL and or c-Met pathways may transgress normal T3 mediated regulation of the cell cycle.

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