Assessment of the Influence of 5-fluorouracil on the SMAD4 Gene Expression, Apoptosis induction and DNA Damage in the Human CACO-2 Cell Line

Abstract

Colorectal cancer (CRC) is the third most common cancer in the world. There are two major distinct precursor lesion pathways: the traditional adenoma–carcinoma pathway leading to most cases CRC, and the serrated neoplasia pathway. SMAD4 gene is involved in adenoma–carcinoma pathway. The protein encoded by the SMAD4 gene is a key downstream signaling mediator in the TGFβ pathway. This pathway has tumor-suppressor functions, including cell-cycle arrest and apoptosis. Its activation in late-stage cancer can promote tumorigenesis, including metastasis and chemoresistance. This study aimed to evaluate the effect of 5-fluorouracil (5-FU) on viability of advanced colorectal cancer cells and establishing whether the test compound may have an effect on the expression level of the SMAD4 gene, DNA damage and apoptosis. Chemotherapy based on 5-FU is used as an adjuvant treatment in most colorectal cancer patients. The results obtained in the study showed that the use of 5-FU in low concentrations may not have a therapeutic effect, and may also influence drug resistance in cancer cells. Moreover, it has been shown that by using 5-FU at higher concentrations and prolonging the exposure time, SMAD4 gene expression is significantly increased which may have an impact on the effectiveness of the therapy.