Crude Extracts, Flavokawain B and Alpinetin Compounds from the Rhizome of Alpinia mutica Induce Cell Death via UCK2 Enzyme Inhibition and in Turn Reduce 18S rRNA Biosynthesis in HT-29 Cells.
Crude Extracts, Flavokawain B and Alpinetin Compounds from the Rhizome of Alpinia mutica Induce Cell Death via UCK2 Enzyme Inhibition and in Turn Reduce 18S rRNA Biosynthesis in HT-29 Cells.
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高良姜根茎中的粗提物、黄酮素 B 和高山姜素化合物通过 UCK2 酶抑制诱导细胞死亡，进而减少 HT-29 细胞中 18S rRNA 的生物合成。
DOI：
10.1371/journal.pone.0170233
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Bello MB
中科院分区：
文献类型：
--
作者：
Malami I;Abdul AB;Abdullah R;Kassim NK;Rosli R;Yeap SK;Waziri P;Etti IC;Bello MB
尿苷-胞苷激酶2是一种在异常细胞生长中过表达的酶，其含义被认为是癌症的标志。由于UCK 2在癌细胞中的选择性表达，选择性抑制这种关键酶需要发现其用于癌症化疗的潜在抑制剂。本研究的目的是证明来自野山姜根茎的天然植物化学物质抑制UCK 2对结直肠癌有用的潜力。在此，我们采用体外研究天然UCK 2抑制剂引起HT-29细胞死亡的有效性。本研究以山姜根茎提取物山姜素B和山姜素复合物为研究对象。研究表明，UCK 2 mRNA在处理的HT-29细胞中的表达显著降低。此外，在所有处理的HT-29细胞中也观察到18 S核糖体RNA表达下调。这通过荧光成像测量活细胞图像中18 S核糖体RNA的表达水平来证实。该研究表明，在UCK 2酶抑制过程中，MDM 2蛋白可能下调，其抑制随后激活p53的表达。p53的表达与G 0/G1期细胞周期进程的阻断直接相关，并且上调Bax、细胞色素c和半胱天冬酶3，而Bcl 2被去调节。在这方面，在处理的HT-29细胞中观察到凋亡诱导和DNA片段化。体外研究的初步结果表明，卡瓦胡椒素B和山姜素的生物活性化合物能够特异性靶向UCK 2酶，诱导细胞周期停滞，随后可能通过干扰MDM 2-p53信号传导途径导致癌细胞死亡。这些现象已经证明，生物活性化合物可用于结肠癌的未来治疗用途。
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.