Abstract

Recent studies show that green tea polyphenols (GTPs), a group of natural products from tea beverages, are able to inhibit the progression of CRC. However, the exact therapeutic constituents and comprehensive acting mechanisms are still poorly understood. This study aims to elucidate the underlying molecular mechanisms in a holistic perspective in virtue of network pharmacology (NP). GTP were mainly consisted of catechins, with small amount of quercetin (˂ 5%), as revealed by UPLC-MS/MS characterization. Powered by NP mining, STAT1, TLR4, MAPK14, CDK2, SERPINE1 and ITGB1, were identified as hub genes constructing a central network underlying the anti-carcinoma effects of GTP. Further phenotype assays validated that GTP inhibited the proliferation and metastasis of CRC cells via multiple mechanisms, including: (1) inducing cell cycle arrest (c-Myc/p21/CDK2 axis), (2) paralyzing cell invasion (ITGB1/N-cadherin/β-catenin/MMP9 axis), (3) promoting apoptosis (STAT1/Bax/Bcl2/Caspase3 axis), (4) initiating ROS-mediated pyroptosis (TLR4/NF-κB/ROS/NLRP3/Caspase1 axis). More importantly, GTP suppressed the tumor progression on xenografted nude mice by acting on the validated hub genes. Collectively, both in vitro and in vivo CRC progression can be inhibited by GTP, which modulates a network consisting multiple signaling pathways governed by the hub genes. These findings demonstrate the functional potential of GTP as a natural product for CRC management, and provide a powerful strategy for exploring holistic mechanisms of food remedies against complex diseases.