Effect of sunitinib on the proliferation and survival of FRTL-5 cells.
- Author:
Won Gu KIM
1
;
Hyun Jeung CHOI
;
Eui Young KIM
;
Ji Hye YIM
;
Ji Min HAN
;
Jin A KIM
;
Tae Yong KIM
;
Young Kee SHONG
;
Won Bae KIM
Author Information
1. Department of Endocrinology & Metabolism, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea. kimwb@amc.seoul.kr
- Publication Type:Original Article
- Keywords:
Sunitinib;
Hypothyroidism;
Cell proliferation;
Cell cycle;
Thyroid-stimulating hormone
- MeSH:
Animals;
Annexin A5;
Apoptosis;
Carcinoma, Renal Cell;
Caspase 3;
Cell Cycle;
Cell Proliferation;
Cyclin D1;
Cyclin-Dependent Kinase 2;
Flow Cytometry;
Gastrointestinal Stromal Tumors;
Humans;
Hypothyroidism;
Immunoblotting;
Indoles;
Protein-Tyrosine Kinases;
Proteins;
Pyrroles;
Rats;
Thyroid Gland;
Thyrotropin
- From:Korean Journal of Medicine
2010;79(5):509-517
- CountryRepublic of Korea
- Language:Korean
-
Abstract:
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 micrometer) by activating caspase-3. G1-S phase arrest was associated with the induction of p27(kip1) and p21(cip1), 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 p27(kip1)/p21(cip1), which are suppressed by TSH under normal conditions. Collectively, these findings suggest that sunitinib may interfere with TSH signaling pathways in normal thyrocytes.
