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Mechanisms of apoptosis in irradiated and sunitinib-treated follicular thyroid cancer cells

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Abstract

The multikinase inhibitor sunitinib (S) seems to have promising potential in the treatment of thyroid cancer. We focused on the impact of S and/or irradiation (R) on mechanisms of apoptosis in follicular thyroid cancer cells. The effects of R, S and their combination were evaluated 2 and 4 days after treatment, using the human thyroid cancer cell line CGTH W-1. The transcription of genes involved in the regulation of apoptosis was investigated using quantitative real-time PCR. Western blot analyses of caspases and survivin were also performed. S elevated BAX (day 4), CASP9, CASP3, BIRC5 (day 4) and PRKACA (day 4) gene expression, whereas the mRNAs of BCL2, CASP8, PRKCA, ERK1, and ERK2 were not significantly changed. S, R and R+S clearly induced caspase-9 protein and elevated caspase-3 activity. Survivin was down-regulated at day 4 in control cells and the expression was blunted by S treatment. R+S induced survivin expression at day 2 followed by a reduction at day 4 of treatment. Sunitinib and the combined application with radiation induced apoptosis in follicular thyroid cancer cells via the intrinsic pathway of apoptosis. In addition, sunitinib might induce apoptosis via decreased expression of the anti-apoptotic protein survivin. These findings suggest the potential use of sunitinib for the treatment of poorly differentiated follicular thyroid carcinomas.

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Abbreviations

BAX:

Bcl-2-associated X protein

DTC:

Differentiated thyroid cancer

ERK1/2:

Extracellular signal-regulated kinases 1 and 2

FLT3:

Fetal liver tyrosine kinase

FTC:

Follicular thyroid cancer

MTC:

Medullary thyroid carcinoma

PARP:

Polyadenosine diphosphate ribose polymerase

PDGFR:

Platelet-derived growth factor receptor

PKA:

Protein kinase A

PKC:

Protein kinase C

PTC:

Papillary thyroid cancer

SDS-PAGE:

Sodium dodecyl sulfate-polyacrylamide gel electrophoresis

TKI:

Tyrosine kinase inhibitor

TNF-R:

Tumor necrosis factor receptor

TSH:

Thyroid-stimulating hormone, also known as thyrotropin

VEGFR:

Vascular endothelial growth factor receptor

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Acknowledgments

The authors would like to thank Mrs. Henriette Dam for her excellent technical assistance. The data presented in this publication are part of the Master’s degree thesis of Elisabeth Warnke prepared during the postgraduate educational program at the Charité-Universitätsmedizin Berlin. We would also like to thank the team at PRS and EJE, Letchworth Garden City, Hertfordshire, UK, for academic proofreading of the manuscript.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Nuclear Medicine, University of Regensburg, Regensburg, Germany

    Jirka Grosse & Christoph Eilles

  2. Clinic for Plastic, Aesthetic and Hand Surgery, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany

    Elisabeth Warnke, Markus Wehland, Jessica Pietsch & Daniela Grimm

  3. Department of Radiooncology, University of Regensburg, Regensburg, Germany

    Fabian Pohl

  4. Division of Hematology, Oncology and Blood & Marrow Transplantation, Children’s Hospital Los Angeles, Keck Medical School, University of Southern California, Los Angeles, CA, USA

    Petra Wise

  5. Medical Research Laboratories, Department of Clinical Medicine, Faculty of Health Sciences, University of Aarhus, Aarhus, Denmark

    Nils E. Magnusson

  6. Institute of Biomedicine, Pharmacology, Aarhus University, Wilhelm Meyers Allé 4, 8000, Aarhus C, Denmark

    Nils E. Magnusson & Daniela Grimm

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  1. Jirka Grosse
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  2. Elisabeth Warnke
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Correspondence to Daniela Grimm.

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Grosse, J., Warnke, E., Wehland, M. et al. Mechanisms of apoptosis in irradiated and sunitinib-treated follicular thyroid cancer cells. Apoptosis 19, 480–490 (2014). https://doi.org/10.1007/s10495-013-0937-0

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