Department of Nutritional Science & Toxicology, University of California Berkeley, Berkeley, CA 94720-3104.
J Nutr Biochem. 2013 Nov;24(11):1882-8. doi: 10.1016/j.jnutbio.2013.05.004. Epub 2013 Aug 19.
3,3'-Diindolylmethane (DIM), an indole derivative from vegetables of the Brassica genus, has antiproliferative activity in breast cancer cells. Part of this activity is thought to be due to DIM inhibition of Akt signaling, but an upstream mechanism of DIM-induced Akt inhibition has not been described. The goals of this study were to investigate the kinetics of inhibition of Akt by physiologically relevant concentrations of DIM and to identify an upstream factor that mediates this effect. Here we report that DIM (5-25 μM) inhibited Akt activation from 30 min to 24h in tumorigenic MDA-MB-231 cells but did not inhibit Akt activation in non-tumorigenic preneoplastic MCF10AT cells. DIM inhibited hepatocyte growth factor (HGF)-induced Akt activation by up to 46%, cell migration by 66% and cell proliferation by up to 54%, but did not inhibit induction of Akt by epidermal growth factor or insulin-like growth factor-1. DIM decreased phosphorylation of the HGF receptor, c-Met, at tyrosines 1234 and 1235, indicating decreased activation of the receptor. This decrease was reversed by pretreatment with inhibitors of p38 or calcineurin. Our results demonstrate the important role of HGF and c-Met in DIM's anti-proliferative effect on breast cancer cells and suggest that DIM could have preventive or clinical value as an inhibitor of c-Met signaling.
3,3'-二吲哚甲烷（DIM）是一种来自芸苔属蔬菜的吲哚衍生物，对乳腺癌细胞具有抗增殖活性。这种活性的一部分被认为是由于 DIM 抑制 Akt 信号通路，但尚未描述 DIM 诱导的 Akt 抑制的上游机制。本研究的目的是研究生理相关浓度的 DIM 对 Akt 的抑制动力学，并鉴定介导这种作用的上游因子。在这里，我们报告 DIM（5-25 μM）抑制了肿瘤发生的 MDA-MB-231 细胞中 Akt 的激活，从 30 分钟到 24 小时，但不抑制非肿瘤发生的前肿瘤 MCF10AT 细胞中 Akt 的激活。DIM 抑制了肝细胞生长因子（HGF）诱导的 Akt 激活高达 46%，细胞迁移高达 66%，细胞增殖高达 54%，但不抑制表皮生长因子或胰岛素样生长因子-1 诱导的 Akt 激活。DIM 降低了 HGF 受体 c-Met 在酪氨酸 1234 和 1235 上的磷酸化，表明受体的激活减少。用 p38 或钙调神经磷酸酶的抑制剂预处理可逆转这种减少。我们的结果表明 HGF 和 c-Met 在 DIM 对乳腺癌细胞的抗增殖作用中起着重要作用，并表明 DIM 作为 c-Met 信号通路的抑制剂可能具有预防或临床价值。
