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.

journal_name

Carcinogenesis

journal_title

Carcinogenesis

authors

Jung SK,Kim JE,Lee SY,Lee MH,Byun S,Kim YA,Lim TG,Reddy K,Huang Z,Bode AM,Lee HJ,Lee KW,Dong Z

doi

10.1093/carcin/bgt266

subject

Has Abstract

pub_date

2014-01-01 00:00:00

pages

123-30

issue

1

eissn

0143-3334

issn

1460-2180

pii

bgt266

journal_volume

35

pub_type

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