Research Institute of Biomedical Engineering and Department of Cell Biology, Daegu Catholic University School of Medicine, Daegu 42472, Republic of Korea.
Department of Biochemistry, College of Korean Medicine, Dong-Eui University, Busan 47227, Republic of Korea.
Int J Mol Sci. 2024 May 25;25(11):5746. doi: 10.3390/ijms25115746.
4-O-Methyl-ascochlorin (MAC), a derivative of the prenyl-phenol antibiotic ascochlorin extracted from the fungus , shows anticarcinogenic effects on various cancer cells. 5-Fluorouracil (5-FU) is used to treat colorectal cancer (CRC); however, its efficacy must be enhanced. In this study, we investigated the molecular mechanisms by which MAC acts synergistically with 5-FU to inhibit cell proliferation and induce apoptosis in CRC cells. MAC enhanced the cytotoxic effects of 5-FU by suppressing the Akt/mTOR/p70S6K and Wnt/β-catenin signaling pathways. It also reduced the viability of 5-FU-resistant (5-FU-R) cells. Furthermore, expression of anti-apoptosis-related proteins and cancer stem-like cell (CSC) markers by 5-FU-R cells decreased in response to MAC. Similar to MAC, the knockdown of CTNNB1 induced apoptosis and reduced expression of mRNA encoding CRC markers in 5-FU-R cells. In summary, these results suggest that MAC and other β-catenin modulators may be useful in overcoming the 5-FU resistance of CRC cells.
4-O-甲基阿克拉霉素（MAC）是从真菌中提取的前酚类抗生素阿克拉霉素的衍生物，对多种癌细胞具有抗癌作用。5-氟尿嘧啶（5-FU）用于治疗结直肠癌（CRC）；然而，其疗效必须增强。在这项研究中，我们研究了 MAC 与 5-FU 协同作用抑制 CRC 细胞增殖并诱导细胞凋亡的分子机制。MAC 通过抑制 Akt/mTOR/p70S6K 和 Wnt/β-catenin 信号通路增强了 5-FU 的细胞毒性作用。它还降低了 5-FU 耐药（5-FU-R）细胞的活力。此外，MAC 降低了 5-FU-R 细胞中抗凋亡相关蛋白和癌症干细胞样细胞（CSC）标志物的表达。与 MAC 类似，CTNNB1 的敲低诱导了 5-FU-R 细胞的凋亡，并降低了 CRC 标志物编码的 mRNA 的表达。总之，这些结果表明，MAC 和其他β-连环蛋白调节剂可能有助于克服 CRC 细胞对 5-FU 的耐药性。
