Cyclopamine Inhibits Cancer Cell Proliferation in Thyroid Cancer Cell Lines / 대한내분비외과학회지

ABSTRACT

PURPOSE: The Hedgehog (HH) signaling pathway is important in development. Recently,ectopic activation of this pathway has been implicated in several forms of solid cancer including basal cell carcinoma, pancreatic cancer, colon cancer, and prostate cancer. There are three HH proteins involved in the pathway Sonic HH, Indiana HH, and Desert HH. Cyclopamine disrupts Sonic HH signaling by inhibition of the seven-transmembrane receptor Smoothened (SMO). Whereas cyclopamine is cytotoxic to several human cancer cells, its effect on thyroid cancer cellsis unknown. We therefore investigated the effect of cyclopamine on cell proliferation in human thyroid cancer cell lines. METHODS: We used fivethyroid cancer cell lines TPC-1 (papillary), FTC-133, FTC-236, FTC-238 (follicular), and XTC-1 (Hurthle cell). The MTT assay and cell cycle analysis were used to evaluate anti-proliferative effects. Tomatidine, a structural analogue of cyclopamine, was used as a control agent. Statistical significance was tested by ANOVA. RESULTS: After 4 days of treatment, the percent inhibition of growth with a concentration of 5, 10, and 20 M cyclopamine in the cell lines were 23.6±4.9%, 66.4±4.7% and 69.3±1.3% in TPC-1 7.5±2.8%, 10.7±3.2% and 49.6±6.4% in FTC-133, 19.2±9.5%, 50.4±4.8% and 60.4±2.0% in FTC- 236 22.8±4.2%, 53.4±5.5% and 63.7±4.8% in FTC- 238 7.6±5.8%, 16.6±2.2%, 24.0±4.3% in XTC-1. Treatment with tomatidine at the same concentrations did not significantly affect cell growth. Exposure to cyclopamine, however, did not affect the cell cycle significantly CONCLUSION: Cyclopamine inhibits cancer cell proliferation in a dose dependent manner in thyroid cancer cell lines. The Hh signaling pathway might be a useful therapeutic target for thyroid cancer.