title: Wogonin induced G1 cell cycle arrest by regulating Wnt/β-catenin signaling pathway and inactivating CDK8 in human colorectal cancer carcinoma cells.
abstract: Wogonin, a naturally occurring mono-flavonoid, has been reported to have tumor therapeutic potential and good selectivity both in vitro and in vivo. Herein, we investigated the anti-proliferation effects and associated mechanisms of wogonin in human colorectal cancer in vitro. The flow-cytometric analysis showed that wogonin induced a G1 phase cell cycle arrest in HCT116 cells in a concentration- and time-dependent manner. Meanwhile, the cell cycle-related proteins, such as cyclin A, E, D1, and CDK2, 4 were down-regulated in wogonin-induced G1 cell cycle arrest. Furthermore, we showed that the anti-proliferation and G1 arrest effect of wogonin on HCT116 cells was associated with deregulation of Wnt/β-catenin signaling pathway. Wogonin-treated cells showed decreased intracellular levels of Wnt proteins, and activated degradation complex to phosphorylated and targeted β-catenin for proteasomal degradation. Wogonin inhibited β-catenin-mediated transcription by interfering in the transcriptional activity of TCF/Lef, and repressing the kinase activity of CDK8 which has been considered as an oncogene involving in the development of colorectal cancers. Moreover, CDK8 siRNA-transfected HCT116 cells showed similar results to wogonin treated cells. Thus, our data suggested that wogonin induced anti-proliferation and G1 arrest via Wnt/β-catenin signaling pathway and it can be developed as a therapeutic agent against human colorectal cancer.
authors.affiliation: State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, People's Republic of China. Electronic address: hlc4113@126.com.
authors.forename: Licheng
authors.initials: L
authors.lastname: He
authors.forename: Na
authors.initials: N
authors.lastname: Lu
authors.forename: Qinsheng
authors.initials: Q
authors.lastname: Dai
authors.forename: Yue
authors.initials: Y
authors.lastname: Zhao
authors.forename: Li
authors.initials: L
authors.lastname: Zhao
authors.forename: Hu
authors.initials: H
authors.lastname: Wang
authors.forename: Zhiyu
authors.initials: Z
authors.lastname: Li
authors.forename: Qidong
authors.initials: Q
authors.lastname: You
authors.forename: Qinglong
authors.initials: Q
authors.lastname: Guo
mesh_terms: D002470:Cell Survival / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D056850:Cyclin-Dependent Kinase 8 / Q000037:antagonists & inhibitors*; D004365:Drugs, Chinese Herbal / Q000494:pharmacology*; D044950:Flavanones / Q000494:pharmacology*; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects*; D045325:HCT116 Cells; D006801:Humans; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000032:analysis; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays
chemical_list: D004365:Drugs, Chinese Herbal; D044950:Flavanones; C497573:LEF1 protein, human; D051821:Lymphoid Enhancer-Binding Factor 1; D056850:Cyclin-Dependent Kinase 8; C085514:wogonin
keywords: APC; AXIN; CDK; CDK8; Colorectal cancer; Dvl; G1 arrest; GSK3β; LRP; Lef; MED12; RB; T-cell factor; TCF; Wogonin; adenomatous polysis coil; axis inhibition protein; cyclin-dependent kinases; disheveled; glycogen synthase kinase 3β; low-density lipoprotein receptor-related protein; lymphoid enhancer factor; mediator of RNA polymerase II transcription, subunit 12 homolog; retinoblastoma protein; β-catenin