title: Fatty acids as natural specific inhibitors of the proto-oncogenic protein Shp2.
abstract: Src homology-2 domain-containing protein tyrosine phosphatase (Shp2), a novel proto-oncogenic protein, is an important target in cancer therapy research. Approximately 2000 plant extracts were screened to find its natural specific inhibitors, with the ethyl acetate (EtOAc) active extract of the root of Angelica dahurica showing considerable inhibitory effects (IC(50)=21.6 mg/L). Bioguided isolation of EtOAc extract led to 13 compounds, including 10 fatty acids and derivatives. All these compounds were isolated from the plant for the first time. The inhibitory effects of these compounds on the enzyme activities of Shp2, VH1-related human protein (VHR), and hematopoietic protein tyrosine phosphatase (HePTP) were investigated. 8Z,11Z-Feptadecadienoic acid (4), 14Z,17Z-tricosadienoic acid (5), caffeic acid (9), and 2-hydroxy-3-[(1-oxododecyl) oxy]propyl-β-d-glucopyranoside (11) showed considerable selective inhibition of Shp2 activity. After treatment of HepG2 cells with the compounds, only compound 5, a polyunsaturated fatty acid, strongly induced poly (ADP-ribose) polymerase (PARP) cleavage in a dose- and time-dependent manner and increased the activities of caspase-3, caspase-8, and caspase-9 at 100 μM. Compound 5 also inhibited colony formation of HepG2 cells in a dose-dependent manner. Thus, this study reported fatty acids as specific Shp2 inhibitors and provided the molecular basis of one active compound as novel potential anticancer drug.
authors.affiliation: School of Pharmaceutical Sciences, Xiamen City Key Laboratory of Metabolism Disease, Xiamen University, Xiamen 361005, PR China.
authors.forename: Dongping
authors.initials: D
authors.lastname: Liu
authors.forename: Guiping
authors.initials: G
authors.lastname: Kong
authors.forename: Quan Cheng
authors.initials: QC
authors.lastname: Chen
authors.forename: Guanghui
authors.initials: G
authors.lastname: Wang
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.forename: Yang
authors.initials: Y
authors.lastname: Xu
authors.forename: Ting
authors.initials: T
authors.lastname: lin
authors.forename: Yingpu
authors.initials: Y
authors.lastname: Tian
authors.forename: Xiaokun
authors.initials: X
authors.lastname: Zhang
authors.forename: Xinsheng
authors.initials: X
authors.lastname: Yao
authors.forename: Gensheng
authors.initials: G
authors.lastname: Feng
authors.forename: Zhongxian
authors.initials: Z
authors.lastname: Lu
authors.forename: Haifeng
authors.initials: H
authors.lastname: Chen
mesh_terms: D029969:Angelica / Q000737:chemistry*; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D005227:Fatty Acids / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology*; D056945:Hep G2 Cells; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy; D010936:Plant Extracts / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D018517:Plant Roots / Q000737:chemistry; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D004791:Enzyme Inhibitors; D005227:Fatty Acids; D010936:Plant Extracts; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11