Thymidylate Synthase Overexpression Drives the Invasive Phenotype in Colon Cancer Cells

Abstract

Thymidylate synthase (TYMS) is the crucial enzymatic precursor for DNA biosynthesis and, therefore, the critical target for numerous types of chemotherapy, including the most frequently applied agent in colon cancer treatment 5-fluorouracil (5-FU). TYMS also seems to be associated with cancer metastasis and acquiring mesenchymal character by tumor cells during epithelial–mesenchymal transition (EMT). Based on that knowledge, we decided to investigate the role of TYMS in the modulation of invasive ability in colon cancer cells, where its effect on cancer metastasis has not been studied in detail before. We employed colon cancer cells isolated from different stages of tumor development, cells undergoing EMT, and TYMS overexpressing cells. The elongation ratio, cell migration, invasion assay, and MMP-7 secretion were applied to analyze the cell behavior. Important epithelial and mesenchymal markers characteristic of EMT were examined at the protein level by Western blot assay. Overall, our study showed a correlation between TYMS level and invasion ability in colon cancer cells and, above all, a crucial role of TYMS in the EMT regulation. We postulate that chemotherapeutics that decrease or inhibit TYMS expression could increase the effectiveness of the therapy in patients with colon cancer, especially in the metastatic stage.

Keywords

• TYMS
• colon cancer
• EMT
• metastasis
• invasion
• MMP-7