Genistein Suppresses v-Src-Driven Proliferative Activity by Arresting the Cell-Cycle at G2/M through Increasing p21 Level in Src-Activated Human Gallbladder Carcinoma cells
Genistein Suppresses v-Src-Driven Proliferative Activity by Arresting the Cell-Cycle at G2/M through Increasing p21 Level in Src-Activated Human Gallbladder Carcinoma cells
复制标题
DOI：
10.1080/01635581.2020.1797835
复制
发表时间：
2020-07-23
影响因子：
2.9
通讯作者：
Nakano, Shuji
中科院分区：
文献类型：
--
作者：
Ono, Misaki;Takeshima, Mikako;Nakano, Shuji
激活的Src与许多人类癌症的发生、发展和转移密切相关。虽然大豆异黄酮具有潜在的抗癌活性，但其对Src致癌活性的影响尚不清楚。利用v-src基因转染的人腺癌细胞(HAG/src3-1)，我们研究了src在染料木素、大豆苷元、黄豆黄素和马酚等异黄酮类化合物抗增殖活性中的作用。金雀异黄素和马酚对HAG/ne3-5细胞生长抑制作用较强，大豆苷元和大豆黄素对HAG/ne3-5细胞生长抑制作用较弱。相反，与HAG/ne3-5细胞相比，Src的激活赋予了对大豆苷元、黄豆黄素或木酚的抗性，但使细胞对金雀异黄素更敏感。金雀异黄素显著地将HAG/src3-1细胞阻滞在G2/M期，而大豆苷元、黄豆黄素和木酚均不能将HAG/src3-1细胞阻滞在任何细胞周期时相。两种异黄酮类化合物均不能诱导细胞凋亡。金雀异黄素可上调p53和p21的表达，降低p21的磷酸化水平，但不影响主要的细胞周期蛋白-CDK复合体的表达。综上所述，金雀异黄素可能被认为是唯一一种可能通过增加p21水平在G2/M期抑制Src诱导的增殖活性的异黄酮类成分，从而为金雀异黄素可能用于预防具有激活的Src的人类癌症提供了机制基础。
Activated Src have been strongly implicated in the development, progression, and metastasis of many human cancers. Although soy isoflavones exhibit potential anticancer activity, effects of isoflavones on oncogenic activity of Src remains unknown. Using v-src-transfected human adenocarcinoma cells (HAG/src3-1), we investigated the functional role of Src in anti-proliferative activity of isoflavones including genistein, daidzein, glycitein and equol. The growth of HAG/neo3-5 vehicle control cells was inhibited potently by genistein and equol, but modestly by daidzein and glycitein. In contrast, Src activation conferred resistance to either daidzein, glycitein or equol, but rendered the cells more sensitive to genistein, compared to HAG/neo3-5 cells. Genistein significantly arrested HAG/src3-1 cells at G2/M, while neither daidzein, glycitein nor equol arrested the cells at any cell cycle phases. Apoptosis was not induced by either isoflavones. Genistein increased the expression levels of p53 and p21 with decreased phosphorylated p21, but did not affect the levels of major cyclin-CDK complexes. Taken together, genistein would be considered as the only isoflavone component that may potentially suppress Src-driven proliferative activity by arresting at G2/M induction through increasing the p21 levels, thus providing the mechanistic rationale for the potential use of genistein for the prevention of human cancers with activated Src.