Luteolin inhibits protein kinase C(epsilon) and c-Src activities and UVB-induced skin cancer.
Luteolin, a flavonoid present in various vegetables including onion and broccoli, has been reported to possess anticarcinogenic effects. However, its chemopreventive effect on UV-induced skin cancer and its mechanism are not fully understood. Herein, we examined the chemopreventive effect and associated mechanisms of luteolin in the JB6 P+ cell line and the SKH-1 hairless mouse model. Luteolin suppressed UVB-induced cyclooxygenase-2 expression and activator protein-1 and nuclear factor-kappaB activity in JB6 P+ cells. Immunoblot and kinase assay data showed that luteolin attenuated protein kinase C(epsilon) (PKC(epsilon)) and Src kinase activities and subsequently inhibited UVB-induced phosphorylation of mitogen-activated protein kinases and the Akt signaling pathway. In addition, pull-down assays revealed that luteolin binds directly to PKC(epsilon) and Src in an ATP-competitive manner. Importantly, luteolin suppressed tumor incidence, multiplicity, and overall size in SKH-1 hairless mice. Analysis of the skin by immunohistochemistry and immunoblotting showed that luteolin-treated groups had a substantial reduction in the levels of cyclooxygenase-2, tumor necrosis factor-alpha, and proliferating cell nuclear antigen compared with groups treated with only UVB. Further analysis using skin lysates showed that luteolin inhibited PKC(epsilon) and Src kinase activity. Together, these data suggest that luteolin exerts potent chemopreventive activity against UVB-induced skin cancer mainly by targeting PKC(epsilon)and Src.
Byun
Sanguine
S
Department of Agricultural Biotechnology, Major in Biomodulation, Seoul National University, Seoul, Republic of Korea.
Lee
Ki Won
KW
Jung
Sung Keun
SK
Lee
Eun Jung
EJ
Hwang
Mun Kyung
MK
Lim
Sung Hwan
SH
Bode
Ann M
AM
Lee
Hyong Joo
HJ
Dong
Zigang
Z
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001667:Binding, Competitive; D000081247:CSK Tyrosine-Protein Kinase; D048708:Cell Growth Processes / Q000187:drug effects / Q000528:radiation effects; D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000096:biosynthesis / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D047311:Luteolin / Q000494:pharmacology*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D051379:Mice; D008812:Mice, Hairless; D016328:NF-kappa B / Q000378:metabolism; D051058:Oncogene Protein v-akt / Q000378:metabolism; D010766:Phosphorylation / Q000528:radiation effects; D051744:Protein Kinase C-epsilon / Q000037:antagonists & inhibitors*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D012867:Skin / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D012878:Skin Neoplasms / Q000201:enzymology* / Q000209:etiology / Q000517:prevention & control*; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D014466:Ultraviolet Rays; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D019061:src-Family Kinases
D016328:NF-kappa B; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; D000255:Adenosine Triphosphate; D051546:Cyclooxygenase 2; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; D051058:Oncogene Protein v-akt; D051744:Protein Kinase C-epsilon; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D047311:Luteolin