Molecular determinants of response to 5-fluorouracil-based chemotherapy in colorectal cancer: The undisputable role of micro-ribonucleic acids

Abstract

5-flurouracil (5-FU)-based chemotherapy is the main pharmacological therapy for advanced colorectal cancer (CRC). Despite significant progress in the treatment of CRC during the last decades, 5-FU drug resistance remains the most important cause of failure in CRC therapy. Resistance to 5-FU is a complex and multistep process. Different mechanisms including microsatellite instability, increased expression level of key enzyme thymidylate synthase and its polymorphism, increased level of 5-FU-activating enzymes and mutation of TP53 are proposed as the main determinants of resistance to 5-FU in CRC cells. Recently, micro-ribonucleic acids (miRNA) and their alterations were found to have a crucial role in 5-FU resistance. In this regard, the miRNA-mediated mechanisms of 5-FU drug resistance reside among the new fields of pharmacogenetics of CRC drug response that has not been completely discovered. Identification of the biological markers that are related to response to 5-FU-based chemotherapy is an emerging field of precision medicine. This approach will have an important role in defining those patients who are most likely to benefit from 5-FU-based chemotherapy in the future. Thereby, the identification of 5-FU drug resistance mechanisms is an essential step to predict and eventually overcome resistance. In the present comprehensive review, we will summarize the latest knowledge regarding the molecular determinants of response to 5-FU-based chemotherapy in CRC by emphasizing the role of miRNAs.

Keywords: 5-flurouracil; Chemotherapy resistance, Thymidylate synthase; Colorectal cancer; Micro-ribonucleic acid; Microsatellite instability; TP53.

Figure 1

Different mechanisms of 5-fluorouracil action. 5-Fluorouracil (5_FU) and its derivative active metabolites exert their antitumor function at the levels of enzyme thymidylate synthase, DNA and RNA, leading to DNA and RNA damage and cell death. TS: Thymidylate synthase; FdUMP: Fluorodeoxyuridine’ monophosphate; FdUDP: Fluorodeoxyuridine diphosphate; FdUTP: Fluorodeoxyuridine triphosphate; FUMP: Fluorouridine monophosphate; FUDP: Fluorouridine diphosphate; FUTP: Fluorouridine triphosphate; CH2THF: 5,10-methylenetetrahydrofolate; dTTP: Deoxythymidine triphosphate; dUMP: Deoxyuridine monophosphate.

Figure 2

Thymidylate synthase inhibition. Fluorodeoxyuridine monophosphate (FdUMP) incorporation into thymidylate synthase in place of deoxyuridine monophosphate (dUMP) results in suppression of thymidylate synthase (TS). Consequently, the synthesis of thymidine monophosphate required for DNA replication and repair is diminished, which leads to deoxyuridine triphosphate (dUTP) imbalances, increased dUTP, DNA damage and finally apoptosis of actively dividing cancerous cells[20]. TK: Thymidylate kinase; CH2THF: 5,10-methylene tetrahydrofolate; dTMP: Deoxythymidine monophosphate; dTTP: Deoxythymidine triphosphate; dNTP: Deoxynucleotide triphosphate.

Figure 3

5-Fluorouracil inhibits ribonucleic acid pseudouridylation including the conversion of uridine to pseudouridine and formation of stable ribonucleoprotein complexes. These actions will interrupt cellular tRNA, pre-mRNA and rRNA production and also post-transcriptional modification, leading to RNA biosynthesis cessation. Moreover, 5-fluorouracil (5-FU) disrupts the assembly and activity of snRNA and protein complexes through its effect on the pseudouridylation of U2 snRNA, thereby inhibiting the splicing of pre-mRNA[21]. Because of the similarity between the 5-FU metabolite fluorouridine triphosphate (FUTP) with uridine triphosphate, FUTP can be identified by RNA polymerases and incorporated into both nuclear and cytoplasmic RNA molecules, interrupting normal RNA processing and function[22]. RNA-based 5-FU toxicity decreases the cellular levels of the nuclear exosome Rrp6 or exosome component 10, a breakdown complex for RNA, banning the effectual turn-over of aberrant RNA transcripts[21]. FUMP: Fluorouridine monophosphate; FUDP: Fluorouridine diphosphate.