A Hybrid Chalcone Combining the Trimethoxyphenyl and Isatinyl Groups   Targets Multiple Oncogenic Proteins and Pathways in Hepatocellular   Carcinoma Cells

doi:10.1371/journal.pone.0161025

CORC > 北京大学 > 生命科学学院

	A Hybrid Chalcone Combining the Trimethoxyphenyl and Isatinyl Groups Targets Multiple Oncogenic Proteins and Pathways in Hepatocellular Carcinoma Cells
	Cao, Lili ; Zhang, Lijun ; Zhao, Xiang ; Zhang, Ye
刊名	PLOS ONE
	2016
关键词	CANCER-CELLS TUBULIN POLYMERIZATION BIOLOGICAL EVALUATION MUTATIONAL LANDSCAPE MOLECULAR THERAPIES ANTITUBULIN AGENTS IN-VIVO NUCLEOLIN KINASE IDENTIFICATION
DOI	10.1371/journal.pone.0161025
英文摘要	Small molecule inhibitors that can simultaneously inhibit multiple oncogenic proteins in essential pathways are promising therapeutic chemicals for hepatocellular carcinoma (HCC). To combine the anticancer effects of combretastatins, chalcones and isatins, we synthesized a novel hybrid molecule 3', 4', 5'-trimethoxy-5-chloro-isatinylchalcone (3MCIC). 3MCIC inhibited proliferation of cultured HepG2 cells, causing rounding-up of the cells and massive vacuole accumulation in the cytoplasm. Paxillin and focal adhesion plaques were downregulated by 3MCIC. Surprisingly, unlike the microtubule (MT)-targeting agent CA-4 that inhibits tubulin polymerization, 3MCIC stabilized tubulin polymers both in living cells and in cell lysates. 3MCIC treatment reduced cyclin B1, CDK1, p-CDK1/2, and Rb, but increased p53 and p21. Moreover, 3MCIC caused GSK3 beta degradation by promoting GSK3 beta-Ser9 phosphorylation. Nevertheless, 3MCIC inhibited the Wnt/beta-catenin pathway by downregulating beta-catenin, c-Myc, cyclin D1 and E2F1. 3MCIC treatment not only activated the caspase-3-dependent apoptotic pathway, but also caused massive autophagy evidenced by rapid and drastic changes of LC3 and p62. 3MCIC also promoted cleavage and maturation of the lysosomal protease cathepsin D. Using ligand-affinity chromatography (LAC), target proteins captured onto the Sephacryl S1000-C-12-3MCIC resins were isolated and analyzed by mass spectrometry (MS). Some of the LAC-MS identified targets, i.e., septin-2, vimentin, pan-cytokeratin, nucleolin, EF1 alpha 1/2, EBP1 (PA2G4), cyclin B1 and GSK3 beta, were further detected by Western blotting. Moreover, both septin-2 and HIF-1 alpha decreased drastically in 3MCIC-treated HepG2 cells. Our data suggest that 3MCIC is a promising anticancer lead compound with novel targeting mechanisms, and also demonstrate the efficiency of LAC-MS based target identification in anticancer drug development.; National Natural Science Foundation of China [31171296]; SCI(E); PubMed; ARTICLE; zhangye@bjmu.edu.cn; 8; e0161025; 11
语种	英语
内容类型	期刊论文
源URL	[http://ir.pku.edu.cn/handle/20.500.11897/491592]
专题	生命科学学院
推荐引用方式 GB/T 7714	Cao, Lili,Zhang, Lijun,Zhao, Xiang,et al. A Hybrid Chalcone Combining the Trimethoxyphenyl and Isatinyl Groups Targets Multiple Oncogenic Proteins and Pathways in Hepatocellular Carcinoma Cells[J]. PLOS ONE,2016.
APA	Cao, Lili,Zhang, Lijun,Zhao, Xiang,&Zhang, Ye.(2016).A Hybrid Chalcone Combining the Trimethoxyphenyl and Isatinyl Groups Targets Multiple Oncogenic Proteins and Pathways in Hepatocellular Carcinoma Cells.PLOS ONE.
MLA	Cao, Lili,et al."A Hybrid Chalcone Combining the Trimethoxyphenyl and Isatinyl Groups Targets Multiple Oncogenic Proteins and Pathways in Hepatocellular Carcinoma Cells".PLOS ONE (2016).