5-Deoxykaempferol plays a potential therapeutic role by targeting multiple signaling pathways in skin cancer

Kyung Mi Lee, Ki Won Lee, Sanguine Byun, Sung Keun Jung, Sang Kwon Seo, Yong Seok Heo, Ann M. Bode, Hyong Joo Lee, Zigang Dong

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

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 UVBinduced skin cancer by targeting Src, PI3K, and RSK2 signaling.

Original languageEnglish
Pages (from-to)454-465
Number of pages12
JournalCancer Prevention Research
Volume3
Issue number4
DOIs
Publication statusPublished - 2010 Apr

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of '5-Deoxykaempferol plays a potential therapeutic role by targeting multiple signaling pathways in skin cancer'. Together they form a unique fingerprint.

  • Cite this