Abstract
BackgroundThe Aurora kinase family members, Aurora-A, -B and -C, are involved in the regulation of mitosis, and alterations in their expression are associated with cell malignant transformation. To date no information on the expression of these proteins in medullary thyroid carcinoma (MTC) are available. We here investigated the expression of the Aurora kinases in human MTC tissues and their potential use as therapeutic targets.MethodsThe expression of the Aurora kinases in 26 MTC tissues at different TNM stages was analyzed at the mRNA level by quantitative RT-PCR. We then evaluated the effects of the Aurora kinase inhibitor MK-0457 on the MTC derived TT cell line proliferation, apoptosis, soft agar colony formation, cell cycle and ploidy.ResultsThe results showed the absence of correlation between tumor tissue levels of any Aurora kinase and tumor stage indicating the lack of prognostic value for these proteins. Treatment with MK-0457 inhibited TT cell proliferation in a time- and dose-dependent manner with IC50 = 49.8 ± 6.6 nM, as well as Aurora kinases phosphorylation of substrates relevant to the mitotic progression. Time-lapse experiments demonstrated that MK-0457-treated cells entered mitosis but were unable to complete it. Cytofluorimetric analysis confirmed that MK-0457 induced accumulation of cells with ≥ 4N DNA content without inducing apoptosis. Finally, MK-0457 prevented the capability of the TT cells to form colonies in soft agar.ConclusionsWe demonstrate that Aurora kinases inhibition hampered growth and tumorigenicity of TT cells, suggesting its potential therapeutic value for MTC treatment.
Highlights
The Aurora kinase family members, Aurora-A, -B and -C, are involved in the regulation of mitosis, and alterations in their expression are associated with cell malignant transformation
No statistically significant variations were observed in the expression of Aurora-A, -B or -C among the different Tumor Node Metastasis (TNM) stages
As reported in figure 1, no differences were found in the Aurora kinases mRNA levels between Rearranged upon Transformation (RET) negative and RET positive tissues
Summary
The Aurora kinase family members, Aurora-A, -B and -C, are involved in the regulation of mitosis, and alterations in their expression are associated with cell malignant transformation. An hallmark of solid tumors including the medullary thyroid carcinoma (MTC), represents the mean by prophase, and as chromosome condensation occurs, Aurora-B forms a complex, called chromosomal passenger complex (CPC), with INCENP (INner CENtromere Protein), survivin and borealin/dasra-B, leading to the phosphorylation of histone H3. The expression and activity of Aurora kinases are precisely regulated during the cell cycle, since their levels are low in G1/S phase and enhanced in the G2/M phase to be decreased after mitosis. This reduction has been shown to involve the ubiquitin-proteasome pathway [9]
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