5-deoxykaempferol plays a potential therapeutic role by targeting multiple signaling pathways in skin cancer.
Nontoxic small molecules with multitargeting effects are believed to have potential in cancer prevention. Dietary phytochemicals were shown to exhibit cancer-preventive effects attributed to their antioxidant capacities. In this report, we show that the natural compound 5-deoxykaempferol (5-DK) exerts a chemopreventive effect on UVB-induced skin carcinogenesis by targeting multiple signaling molecules. 5-DK suppressed the UVB-induced expression of cyclooxygenase-2 (COX-2) and vascular endothelial growth factor in mouse skin epidermal JB6 P+ cells. Moreover, 5-DK inhibited phosphorylation of MKK3/6, MKK4, and Akt, but had no effect on phosphorylation of Src, extracellular signal-regulated kinases, or ribosomal S6 kinase (RSK). However, 5-DK affected multiple targets by reducing Src, phosphoinositide 3-kinase (PI3K), and RSK2 activities. In particular, pull-down assays revealed that 5-DK specifically bound to and competed with ATP for binding with Src, PI3K, and RSK2. Exposure to 5-DK significantly suppressed UVB-induced tumorigenesis in mouse skin in a dose-dependent manner, and it inhibited the UVB-induced expression of COX-2, proliferating cell nuclear antigen, vascular endothelial growth factor, and matrix metalloproteinase-9. Our data suggest that 5-DK docks at the ATP-binding site of Src, PI3K, and RSK2. For RSK2, the ATP-binding site is located between the N- and C-lobes of the kinase domain. Taken together, our results indicate that 5-DK holds promise for the treatment of UVB-induced skin cancer by targeting Src, PI3K, and RSK2 signaling.
Lee
Kyung Mi
KM
Department of Agricultural Biotechnology, Seoul National University, Seoul, Republic of Korea.
Lee
Ki Won
KW
Byun
Sanguine
S
Jung
Sung Keun
SK
Seo
Sang Kwon
SK
Heo
Yong-Seok
YS
Bode
Ann M
AM
Lee
Hyong Joo
HJ
Dong
Zigang
Z
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D051546:Cyclooxygenase 2 / Q000096:biosynthesis / Q000187:drug effects; D007887:Fabaceae; D005419:Flavonoids / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D007150:Immunohistochemistry; D044949:Kaempferols / Q000494:pharmacology*; D051379:Mice; D008812:Mice, Hairless; D019869:Phosphatidylinositol 3-Kinases / Q000187:drug effects / Q000378:metabolism; D008517:Phytotherapy; D010936:Plant Extracts / Q000494:pharmacology*; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000187:drug effects; D019061:src-Family Kinases / Q000187:drug effects / Q000378:metabolism
C550286:5-deoxykaempferol; D000970:Antineoplastic Agents; D005419:Flavonoids; D044949:Kaempferols; D010936:Plant Extracts; D042461:Vascular Endothelial Growth Factor A; D051546:Cyclooxygenase 2; D019869:Phosphatidylinositol 3-Kinases; D019061:src-Family Kinases; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C069330:ribosomal protein S6 kinase, 90kDa, polypeptide 3