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

Sung Keun Jung, Jong Eun Kim, Sung Young Lee, Mee Hyun Lee, Sanguine Byun, Young A. Kim, Tae Gyu Lim, Kanamata Reddy, Zunnan Huang, Ann M. Bode, Hyong Joo Lee, Ki Won Lee, Zigang Dong

Research output: Contribution to journalArticlepeer-review

26 Citations (Scopus)


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 pseudoacacia, 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 p70S6K, 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.

Original languageEnglish
Pages (from-to)123-130
Number of pages8
Issue number1
Publication statusPublished - 2014 Jan

Bibliographical note

Funding Information:
Hormel Foundation; Leap Research Program (No. 2010-0029233), Basic Science Research Program (NRF-2011-357-F00044) and Global Frontier Project grant (NRF-M1AXA002-2012M3A6A4054949) through the National Research Foundation of Korea funded by the Ministry of Education, Science and Technology, Republic of Korea; Korea Food Research Institute; National Institutes of Health grants (CA120388, R37CA081064, CA1666011, CA172457).

All Science Journal Classification (ASJC) codes

  • Cancer Research


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