Phosphatidylinositol 3-kinase, a novel target molecule for the inhibitory effects of kaempferol on neoplastic cell transformation.
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 microM KF. The activation of activator protein-1 and nuclear factor-kappaB 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.
Department of Agricultural Biotechnology, Seoul National University, Republic of Korea.
Kyung Mi
KM
Lee
Dong Eun
DE
Lee
Sang Kwon
SK
Seo
Mun Kyung
MK
Hwang
Yong-Seok
YS
Heo
Ki Won
KW
Lee
Hyong Joo
HJ
Lee
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D018929:Cell Culture Techniques; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D004817:Epidermis / Q000187:drug effects / Q000502:physiology; D044949:Kaempferols / Q000494:pharmacology*; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D016328:NF-kappa B / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000187:drug effects / Q000378:metabolism*; D010957:Plasmids; D018808:Transcription Factor AP-1 / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects
D044949:Kaempferols; D016328:NF-kappa B; D018808:Transcription Factor AP-1; C006552:kaempferol; D000255:Adenosine Triphosphate; D008156:Luciferases; D019869:Phosphatidylinositol 3-Kinases