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KMID : 0882420100790050509
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Korean Journal of Medicine
2010 Volume.79 No. 5 p.509 ~ p.517
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Effect of sunitinib on the proliferation and survival of FRTL-5 cells
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Kim Won-Gu
Choi Hyun-Jeung
Kim Eui-Young
Yim Ji-Hye
Han Ji-Min
Kim Jin-A
Kim Tae-Yong
Shong Young-Kee
Kim Won-Bae
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Abstract
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Background/Aims: Hypothyroidism has been reported in 36~85% of patients treated with sunitinib for renal cell carcinoma or gastrointestinal stromal tumor. However, the mechanism behind this hypothyroidism is unclear. This study evaluated the effects of sunitinib, a multi-target tyrosine kinase inhibitor, on the survival and proliferation of thyrocytes using FRTL-5 rat thyroid cells.
Methods: We examined the effect of sunitinib on cell proliferation in the presence and absence of thyroid stimulating hormone (TSH) in a colorimetric assay. Effects on the cell cycle were evaluated by flow cytometry, and on apoptosis using an annexin V apoptosis assay kit and by immunoblotting for caspase-3. Immunoblotting was also used to evaluate changes in the levels of intracellular proteins associated with the G1-S phase of the cell cycle.
Results: Sunitinib suppressed the proliferation of FRTL-5 cells in a dose- and time-dependent manner. This suppressive effect was enhanced by the presence of TSH (1 mU/mL). Sunitinib was subsequently shown, in flow cytometric analyses, to arrest the cell cycle at the G1-S phase. Furthermore, it induced apoptosis at a high concentration (15 μM) by activating caspase-3. G1-S phase arrest was associated with the induction of p27kip1 and p21cip1, whose expression is suppressed by TSH under control conditions. Sunitinib also decreased intracellular levels of cyclin D1 and cyclin-dependent kinase 2 in FRTL-5 cells.
Conclusions: Sunitinib induced apoptosis in and suppressed the proliferation of FRTL-5 cells. Its suppression of proliferation was further enhanced by the presence of TSH. Sunitinib arrested the cell cycle in the G1-S phase by inducing the expression of p27kip1/p21cip1, which are suppressed by TSH under normal conditions. Collectively, these findings suggest that sunitinib may interfere with TSH signaling pathways in normal thyrocytes.
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KEYWORD
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Sunitinib, Hypothyroidism, Cell proliferation, Cell cycle, Thyroid-stimulating hormone
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