The P110 subunit of PI3-K is a therapeutic target of acacetin in skin cancer

• Published in: Carcinogenesis (New York) Vol. 35; no. 1; pp. 123 - 130
• Main Authors: Jung, Sung Keun, Kim, Jong Eun, Lee, Sung-Young, Lee, Mee Hyun, Byun, Sanguine, Kim, Young A, Lim, Tae Gyu, Reddy, Kanamata, Huang, Zunnan, Bode, Ann M, Lee, Hyong Joo, Lee, Ki Won, Dong, Zigang
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 01.01.2014
• Subjects: Adenosine Triphosphate - metabolism; Animals; Antineoplastic Agents, Phytogenic - pharmacology; Cell Proliferation - drug effects; Cell Transformation, Neoplastic - drug effects; Class Ia Phosphatidylinositol 3-Kinase - antagonists & inhibitors; Class Ia Phosphatidylinositol 3-Kinase - metabolism; Enzyme Inhibitors - pharmacology; Epidermal Growth Factor - pharmacology; Flavones - metabolism; Flavones - pharmacology; Mice; Mice, Nude; Molecular Docking Simulation; Original Manuscript; Phosphatidylinositol 3-Kinases - antagonists & inhibitors; Phosphatidylinositol 3-Kinases - metabolism; Phosphorylation - drug effects; Proto-Oncogene Proteins c-akt - metabolism; Skin Neoplasms - drug therapy; Skin Neoplasms - metabolism; Tumor Cells, Cultured; Xenograft Model Antitumor Assays
• ISSN: 0143-3334; 1460-2180
• DOI: 10.1093/carcin/bgt266

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.