Endocrine Abstracts

Antiproliferative actions of 1,25(OH)₂D₃ (1,25D), the active form of Vitamin D, are reported in various types of cancer, whereas little is known about the underlying molecular mechanism. Interestingly, in non thyroid-cancer cells, stimulation with 1,25D has been shown to affect cell proliferation in a Sirtuin 1 (Sirt1) dependent manner. Sirtuin histon deacetylases are key factors in cell metabolism recently found to be overexpressed in different carcinomas. The aim of the present study was to investigate the relevance of Sirt1 and the existence of a 1,25D-Sirt1 pathway in differentiated thyroid carcinoma (DTC). Sirt1 gene expression was analyzed in human DTC (n=13) and goiter tissue (n=11) by quantitative real-time PCR with CT-value defined as 2^{−[CTSirt1–CTGAPDH]} ×10⁶. Furthermore, cells of papillary thyroid cancer cell line BCPAP were cultivated at 5×10⁵ cell test approaches and incubated with or without (=Co) the following stimuli: 1,25D, Sirt1 inhibitor Ex-527 (Ex) or Ex+1,25D. After 96h, cell proliferation was measured by Neubauer counting chamber and Sirt1 gene expression was analyzed. In order to investigate the influence of 1,25D action on Sirt1 activity, stimulation with 1,25D+Ex was compared to stimulation with 1,25D alone. DTC showed enhanced Sirt1 expression in comparison to goiter tissue (DTC vs. goiter, 1.9×10⁴ vs 7.7×10³ 2^{−[CTSirt1–CTGAPDH]} ×10⁶ p_c: 4×10⁻²). Moreover, in cell culture 1,25D inhibited DTC proliferation (mean cell count: 1,25D vs Co=5.6×10⁵ vs 1.2×10⁶ cells/ml_, p_c: 6×10⁻⁴). Interestingly, addition of Ex to 1,25D reduced the cell suppressive effect of 1,25D (Ex+1,25D vs 1,25D=9.5×10⁵ vs 5.6×10⁵ cells/ml, p_c: 6×10⁻⁴). However, none of the stimuli affect Sirt1 gene expression. This study indicates Sirt1 to be overexpressed in DTC. Furthermore, antiproliferative actions of 1,25D on papillary thyroid cancer cells appear to be dependent on Sirt1 activity, indicating the existence of a 1,25D regulated Sirt1 signal transduction in thyroid cancer cells.