Department of Nutrition, University of California, Davis, CA, USA; Department of Environmental Toxicology, University of California, Davis, CA, USA; College of Food Science and Technology, Huazhong Agricultural University, Wuhan, Hubei, China.
College of Food Science and Technology, Huazhong Agricultural University, Wuhan, Hubei, China.
Biochem Pharmacol. 2020 May;175:113923. doi: 10.1016/j.bcp.2020.113923. Epub 2020 Mar 23.
Colorectal cancer (CRC) is one of the most common cancers worldwide. Epidemiological studies indicate that consumption of fruits and vegetables containing procyanidins is associated with lower CRC risk. This study investigated the capacity of two dimeric procyanidins composed of epicatechin gallate (ECG) or epigallocatechin gallate (EGCG) isolated from persimmons, to inhibit CRC cell growth and promote apoptosis, characterizing the underlying mechanisms. ECG and EGCG dimers reduced the growth of five human CRC cell lines in a concentration (10-60 μM)- and time (24-72 h)-dependent manner, with a 72 h-IC value in Caco-2 cells of 10 and 30 μM, respectively. ECG and EGCG dimers inhibited Caco-2 cell proliferation by arresting the cell cycle in G/M phase and by inducing apoptosis via the mitochondrial pathway. In addition, ECG and EGCG dimers inhibited cell migration, invasion, and adhesion, decreasing the activity of matrix metalloproteinases (MMP-2/9). Mechanistically, ECG and EGCG dimers inhibited the activation of lipid raft-associated epidermal growth factor (EGF) receptor (EGFR), without affecting its localization at lipid rafts. In particular, ECG and EGCG dimers reduced EGFR phosphorylation at Tyr residue, prevented EGFR dimerization and activation upon stimulation, and induced EGFR internalization both in the absence and presence of EGF. Furthermore, ECG and EGCG dimers increased EGFR phosphorylation at Tyr residue, providing a docking site for ubiquitin ligase c-Cbl and induced EGFR degradation by the proteasome. Downstream of EGFR, ECG and EGCG dimers inhibited the activation of the MEK/ERK1/2 and PI3K/AKT signaling pathways, downregulating proteins involved in the modulation of cell survival. In conclusion, ECG and EGCG dimers reduced CRC cell growth by inhibiting EGFR activation at multiple steps, including the disruption of lipid rafts integrity and promoting EGFR degradation. These results shed light on a potential molecular mechanism on how procyanidins-rich diets may lower CRC risk.
结直肠癌（CRC）是全球最常见的癌症之一。流行病学研究表明，食用富含原花青素的水果和蔬菜与降低 CRC 风险有关。本研究探讨了从柿子中分离得到的两种二聚原花青素（ECG 和 EGCG）抑制 CRC 细胞生长和促进细胞凋亡的能力，并对其潜在机制进行了表征。ECG 和 EGCG 二聚体以浓度（10-60 μM）和时间（24-72 h）依赖性方式降低了 5 个人 CRC 细胞系的生长，在 Caco-2 细胞中 72 h 的 IC 值分别为 10 和 30 μM。ECG 和 EGCG 二聚体通过将细胞周期阻滞在 G2/M 期和通过线粒体途径诱导细胞凋亡来抑制 Caco-2 细胞增殖。此外，ECG 和 EGCG 二聚体抑制细胞迁移、侵袭和黏附，降低基质金属蛋白酶（MMP-2/9）的活性。在机制上，ECG 和 EGCG 二聚体抑制了富含脂筏的表皮生长因子（EGF）受体（EGFR）的激活，而不影响其在脂筏上的定位。特别是，ECG 和 EGCG 二聚体降低了 Tyr 残基上 EGFR 的磷酸化，阻止了 EGFR 二聚化和刺激后的激活，并在没有 EGF 的情况下诱导 EGFR 内化。此外，ECG 和 EGCG 二聚体增加了 Tyr 残基上 EGFR 的磷酸化，为泛素连接酶 c-Cbl 提供了一个对接位点，并通过蛋白酶体诱导 EGFR 降解。在 EGFR 下游，ECG 和 EGCG 二聚体抑制了 MEK/ERK1/2 和 PI3K/AKT 信号通路的激活，下调了参与调节细胞存活的蛋白。总之，ECG 和 EGCG 二聚体通过抑制 EGFR 在多个步骤的激活来减少 CRC 细胞的生长，包括破坏脂筏的完整性和促进 EGFR 降解。这些结果揭示了富含原花青素的饮食如何降低 CRC 风险的潜在分子机制。
