Journal Article

Phosphatidylinositol 3-kinase, a novel target molecule for the inhibitory effects of kaempferol on neoplastic cell transformation

Kyung Mi Lee, Dong Eun Lee, Sang Kwon Seo, Mun Kyung Hwang, Yong-Seok Heo, Ki Won Lee and Hyong Joo Lee

in Carcinogenesis

Volume 31, issue 8, pages 1338-1343
Published in print August 2010 | ISSN: 0143-3334
Published online June 2010 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgq102
Phosphatidylinositol 3-kinase, a novel target molecule for the inhibitory effects of kaempferol on neoplastic cell transformation

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Kaempferol (KF), which is a natural dietary flavonoid, has potential beneficial effects as a chemopreventive agent for critical health conditions, such as cancer. However, the molecular mechanisms underlying the activity of KF remain unknown. We report on the inhibition of neoplastic cell transformation by KF through the suppression of phosphatidylinositol 3-kinase (PI3K) activity. Epidermal growth factor (EGF)-induced neoplastic transformation of mouse epidermal JB6 P+ cells was inhibited by 40 μM KF. The activation of activator protein-1 and nuclear factor-κB induced by EGF was also attenuated by KF. The EGF-induced phosphorylation of Akt (protein kinase B) was completely suppressed by KF, although extracellular signal-regulated kinase, p38, c-Jun N-terminal kinase and p90 ribosomal S6 kinase were unaffected by KF. Kinase assay data revealed that KF bound directly to PI3K, which is upstream of Akt, and suppressed its activity. Furthermore, KF inhibited ultraviolet B (UVB)-induced PI3K activity and attenuated UVB-induced phosphorylation of Akt. Our results suggest that KF docks at the adenosine triphosphate-binding site of PI3K, which is located between the N-lobe and C-lobe of the kinase domain. Inhibition by KF of PI3K, which is an important factor in carcinogenesis, and its downstream effects may explain the chemopreventive action of KF.

Journal Article.  4756 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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