Suppression of TWIST1 enhances the sensitivity of colon cancer cells to 5-fluorouracil |
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| Affiliation: | 1. Department of Molecular Medicine, Medical University of Gdansk, 80-211 Gdansk, Poland;2. Departemnt of Laboratory Medicine, Medical University of Gdansk, 80-211 Gdansk, Poland;1. Department of Diagnostic Radiology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan;2. Department of Hepatobiliary and Pancreatic Surgery, National Cancer Center Hospital, Tokyo, Japan;3. Department of Gastric surgery, National Cancer Center Hospital, Tokyo, Japan;4. Course of Advanced Clinical Research of Cancer, Juntendo University Graduate School of Medicine, Tokyo, Japan;1. Liver Transplantation Center of the First Affiliated Hospital and Cancer Center, Nanjing Medical University, Nanjing, Jiangsu Province, P.R. China;2. Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology and Pathology, Cancer Center, UCSD School of Medicine, La Jolla, CA 92093-0723, USA;1. Department of Immunology, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan;2. Division of Hematopoiesis, Center for AIDS Research, Kumamoto University, 2-2-1 Honjo, Kumamoto 860-0811, Japan;3. Cooperative Major in Advanced Health Science, Tokyo University of Agriculture and Technology/Waseda University Graduate School of Collaborative Education Curriculum, 3-4-1 Okubo, Shinjuku-ku, Tokyo 169-8555, Japan;4. Japan Foundation for AIDS Prevention, 1-3-12 Misakimachi, Chiyoda-ku, Tokyo 101-0061, Japan;5. Department of Medical Technology, School of Human Sciences, Tokyo University of Technology, 5-23-22 Nishikamata, Ota-ku, Tokyo 144-8535, Japan;1. Department of Plastic Surgery, MedStar Georgetown University Hospital, Washington, DC;2. Department of Surgery, MedStar Georgetown University Hospital, Washington, DC;3. Division of Plastic and Reconstructive Surgery, Department of Surgery, George Washington University Hospital, Washington, DC |
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| Abstract: | The 5-fluorouracil (5FU)-based adjuvant chemotherapy improves the survival of patients with colorectal cancer, however the main obstacle affecting its effectiveness is a drug resistance. Our study aimed to investigate the impact of TWIST1 silencing on the sensitivity of cancer cells to 5FU. The suppression of TWIST1 expression in human colon cancer HT29 and HCT116 cell lines was achieved by transduction with lentiviral vector carrying the TWIST1 silencing sequence (pLL3.7-shTWIST1). The suppression of TWIST1 expression induced changes in the expression pattern of epithelial to mesenchymal transition markers, reduced the cells proliferation rate, increased their sensitivity to serum withdrawn, and increased the cytotoxic effect of 5FU. However, significantly higher 5FU cytotoxicity was observed in HT29 cell cultures. Cells with silenced TWIST1 displayed altered expression of enzymes metabolizing 5FU. The expression level of dihydropyrimidine dehydrogenase, and thymidylate synthase decreased significantly in HT29 shTWIST1 cells, but not in HCT116 shTWIST1 cells. On the other hand, significant increases in the expression levels of thymidine phosphorylase, and uridine phosphorylase 1 were seen in both cell lines with suppressed expression of TWIST1. The changes in enzymes expression were mirrored by enzymatic activities. In conclusion, our observations point to TWIST1 as a target protein to enhance the sensitivity of colorectal cancer cells to 5FU. |
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| Keywords: | 5-fluorouracil Colon cancer |
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