Abstract
Uridine-cytidine kinase 2 is an enzyme that is overexpressed in abnormal cell growth and its implication is considered a hallmark of cancer. Due to the selective expression of UCK2 in cancer cells, a selective inhibition of this key enzyme necessitates the discovery of its potential inhibitors for cancer chemotherapy. The present study was carried out to demonstrate the potentials of natural phytochemicals from the rhizome of Alpinia mutica to inhibit UCK2 useful for colorectal cancer. Here, we employed the used of in vitro to investigate the effectiveness of natural UCK2 inhibitors to cause HT-29 cell death. Extracts, flavokawain B, and alpinetin compound from the rhizome of Alpinia mutica was used in the study. The study demonstrated that the expression of UCK2 mRNA were substantially reduced in treated HT-29 cells. In addition, downregulation in expression of 18S ribosomal RNA was also observed in all treated HT-29 cells. This was confirmed by fluorescence imaging to measure the level of expression of 18S ribosomal RNA in live cell images. The study suggests the possibility of MDM2 protein was downregulated and its suppression subsequently activates the expression of p53 during inhibition of UCK2 enzyme. The expression of p53 is directly linked to a blockage of cell cycle progression at G0/G1 phase and upregulates Bax, cytochrome c, and caspase 3 while Bcl2 was deregulated. In this respect, apoptosis induction and DNA fragmentation were observed in treated HT-29 cells. Initial results from in vitro studies have shown the ability of the bioactive compounds of flavokawain B and alpinetin to target UCK2 enzyme specifically, inducing cell cycle arrest and subsequently leading to cancer cell death, possibly through interfering the MDM2-p53 signalling pathway. These phenomena have proven that the bioactive compounds could be useful for future therapeutic use in colon cancer.
Highlights
Uridine-cytidine kinase 2 (UCK2) is an enzyme that catalyses the conversion of uridine and cytidine to their monophosphate form of uridine and cytidine in an alternative salvage pathway of pyrimidine biosynthesis [1]
The results showed that treatment with flavokawain B (FKB) inhibit cell growth at IC50 values of 102.3 μM (29.03 μg/mL) and 189.08 (53.7 μg/mL) for the mammalian liver and kidney cells, respectively
These compounds may possibly possess stereochemistry and molecular structures near similar or parallel to FKB or APN. The presence of these compounds that mimics parallel mechanism of action to FKB and APN in inhibiting the UCK2 enzyme, which subsequently induces apoptosis in a similar manner to suggest strongly that it may be possibly be this presence of FKB and APN compounds in the extracts that contributed to the anticancer properties of the crude extracts
Summary
Uridine-cytidine kinase 2 (UCK2) is an enzyme that catalyses the conversion of uridine and cytidine to their monophosphate form of uridine and cytidine in an alternative salvage pathway of pyrimidine biosynthesis [1]. A formation of 5’-triphosphate form of uridine and cytidine nucleosides are an essential requirement in gene replication Overexpression of this enzyme have been implicated in several cancers and it is considered a hallmark of cancer. MDM2 is in turn regulated by ribosomal proteins (RPs) that binds and suppress the MDM2 E3 ubiquitin ligase activity resulting in the stabilization and activation of p53 [9]. These ribosomal proteins are found in stoichiometric amounts in the ribosome, they are abundantly expressed in metabolically active cells undergoing protein synthesis [9,10]. In response to the instability of ribosomal biogenesis such as the depletion of nucleotides, many RPs are released from the nucleolus and block MDM2 that targets p53 for degradation, this leads to p53 induction and cell cycle arrest [14]
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