Division of Applied Biological Chemistry, Department of Bioscience and Biotechnology, Faculty of Agriculture, Kyushu University, Fukuoka, Japan; Institute of Fruit Tree and Tea Science, National Agriculture and Food Research Organization (NARO), Ibaraki, Japan.
Division of Applied Biological Chemistry, Department of Bioscience and Biotechnology, Faculty of Agriculture, Kyushu University, Fukuoka, Japan.
J Nutr Biochem. 2022 Feb;100:108910. doi: 10.1016/j.jnutbio.2021.108910. Epub 2021 Nov 18.
Isoflavone is a species of polyphenol found mainly in soy and soy products. Many studies have demonstrated its estrogen receptor (ER)-dependent action. Equol is an intestinal metabolite of a major soy isoflavone daidzein. We aimed to elucidate the mechanism for ER-independent actions of equol. Equol has been shown to inhibit proliferation of HeLa human cervical cancer cells and mouse melanoma B16 cells in an ER-independent manner. Using functional genetic screening, PAP associated domain containing 5 (PAPD5), which is a non-canonical poly(A) polymerase, was identified as an essential molecule in the ER-independent action. While peroral administration of equol inhibited tumor growth of control B16 cells subcutaneously inoculated in mice, it had little effect on the growth of PAPD5-ablated B16 cells. Intriguingly, equol progressed tumor growth of the PAPD5-ablated human breast cancer MCF-7 cells, which have high ERα expression. Equol has been found to induce polyadenylation of snoRNAs in a PAPD5-depdendent manner. Furthermore, peroral equol administration increased microRNA miR-320a expression in tumors. Together, these results suggest that equol may have a dual effect on ER-positive cancer cells, acting with, antiproliferative activity through PAPD5 and exhibiting proliferative activity via ERα and the former could be associated with miR-320a.
异黄酮是一种主要存在于大豆及其制品中的多酚类物质。许多研究表明它具有雌激素受体（ER）依赖性作用。黄豆苷元是大豆异黄酮染料木黄酮的主要肠道代谢物。我们旨在阐明黄豆苷元的非 ER 依赖性作用机制。黄豆苷元已被证明以非 ER 依赖性方式抑制人宫颈癌细胞 HeLa 和小鼠黑色素瘤 B16 细胞的增殖。通过功能遗传筛选，发现 PAP 相关结构域包含 5（PAPD5），它是一种非典型的多（A）聚合酶，是 ER 非依赖性作用的必需分子。虽然黄豆苷元口服给药抑制了皮下接种在小鼠中的对照 B16 细胞的肿瘤生长，但对 PAPD5 缺失的 B16 细胞的生长几乎没有影响。有趣的是，黄豆苷元促进了 PAPD5 缺失的高 ERα 表达的人乳腺癌 MCF-7 细胞的肿瘤生长。已发现黄豆苷元以 PAPD5 依赖的方式诱导 snoRNAs 的多聚腺苷酸化。此外，口服黄豆苷元给药增加了肿瘤中 microRNA miR-320a 的表达。总之，这些结果表明，黄豆苷元可能对 ER 阳性癌细胞具有双重作用，通过 PAPD5 发挥抗增殖活性，并通过 ERα 和前者发挥增殖活性，而后者可能与 miR-320a 相关。
