title: The P110 subunit of PI3-K is a therapeutic target of acacetin in skin cancer.
abstract: The identification of primary molecular targets of cancer-preventive phytochemicals is essential for a comprehensive understanding of their mechanism of action. In the present study, we investigated the chemopreventive effects and molecular targets of acacetin, a flavonoid found in Robinia p seudoacacia, also known as black locust. Acacetin treatment significantly suppressed epidermal growth factor (EGF)-induced cell transformation. Immunoblot analysis revealed that acacetin attenuated EGF-induced phosphorylation of Akt and p70(S6K), which are downstream effectors of phosphatidylinositol 3-kinase (PI3-K). An immunoprecipitation kinase assay of PI3-K and pull-down assay results demonstrated that acacetin substantially inhibits PI3-K activity by direct physical binding. Acacetin exhibited stronger inhibitory effects against anchorage-dependent and -independent cell growth in cells expressing higher PI3-K activity compared with those exhibiting relatively low PI3-K activity. Binding assay data combined with computational modeling suggest that acacetin binds in an adenosine triphosphate (ATP)-competitive manner with the p110α subunit of PI3-K and interacts with Val828, Glu826, Asp911, Trp760, Ile777, Ile825, Tyr813, Ile910 and Met900 residues. Acacetin was also found to significantly reduce SK-MEL-28 tumor growth and Akt phosphorylation in vivo. Taken together, these results indicate that acacetin is an ATP-competitive PI3-K inhibitor and a promising agent for melanoma chemoprevention.
authors.affiliation: The Hormel Institute, University of Minnesota, 801 16th Ave NE, Austin, MN 55912, USA.
authors.forename: Sung Keun
authors.initials: SK
authors.lastname: Jung
authors.forename: Jong Eun
authors.initials: JE
authors.lastname: Kim
authors.forename: Sung-Young
authors.initials: SY
authors.lastname: Lee
authors.forename: Mee Hyun
authors.initials: MH
authors.lastname: Lee
authors.forename: Sanguine
authors.initials: S
authors.lastname: Byun
authors.forename: Young A
authors.initials: YA
authors.lastname: Kim
authors.forename: Tae Gyu
authors.initials: TG
authors.lastname: Lim
authors.forename: Kanamata
authors.initials: K
authors.lastname: Reddy
authors.forename: Zunnan
authors.initials: Z
authors.lastname: Huang
authors.forename: Ann M
authors.initials: AM
authors.lastname: Bode
authors.forename: Hyong Joo
authors.initials: HJ
authors.lastname: Lee
authors.forename: Ki Won
authors.initials: KW
authors.lastname: Lee
authors.forename: Zigang
authors.initials: Z
authors.lastname: Dong
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D058543:Class Ia Phosphatidylinositol 3-Kinase / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004815:Epidermal Growth Factor / Q000494:pharmacology; D047309:Flavones / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D062105:Molecular Docking Simulation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000255:Adenosine Triphosphate; D000972:Antineoplastic Agents, Phytogenic; D058543:Class Ia Phosphatidylinositol 3-Kinase; D004791:Enzyme Inhibitors; D004815:Epidermal Growth Factor; D047309:Flavones; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; C023717:acacetin
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