Luteolin Inhibits Protein Kinase Cϵ and c-Src Activities and UVB-Induced Skin Cancer

Abstract

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-κB activity in JB6 P+ cells. Immunoblot and kinase assay data showed that luteolin attenuated protein kinase Cε (PKCε) 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 PKCε 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 luteolintreated groups had a substantial reduction in the levels of cyclooxygenase-2, tumor necrosis factor-α, and proliferating cell nuclear antigen compared with groups treated with only UVB. Further analysis using skin lysates showed that luteolin inhibited PKCε and Src kinase activity. Together, these data suggest that luteolin exerts potent chemopreventive activity against UVB-induced skin cancer mainly by targeting PKCε and Src.

Preparation and characterization of monomethoxy poly(ethylene glycol)-poly(ε-caprolactone) micelles for the solubilization and in vivo delivery of luteolin

“…The anticancer effect of Lu also is associated with inducing apoptosis, which involves redox regulation, DNA damage, and protein kinases in inhibiting the proliferation of cancer cells and suppressing metastasis and angiogenesis. 6,[10][11][12][13][14][15][16][17] Moreover, Lu has cytotoxicity in cancer cells or immortalized cells, but not in normal cells, meaning that it has fewer side effects when used in treating cancer. 8,12,18 Yet Lu has some drawbacks, such as poor water solubility (,2 × 10 −2 µmol/mL), 19 low oral absorption, 20 and bioavailability (30.4% in rats), 21 which limit its clinical application.…”

Impact of butyrate on PKM2 and HSP90β expression in human colon tissues of different transformation stages: a comparison of gene and protein data

“…So far, only indirect evidence is given regarding a regulation by bioactive food agents (Kim and Milner 2011). Components like luteolin (Byun et al 2010), delphinidin (Fridrich et al 2008), or butyrate (Hirsch et al 2006) were reported to inhibit oncogenic tyrosine kinases that are known to participate in the regulation of PKM2 activity (Hitosugi et al 2009). …”

Luteolin reduces the invasive potential of malignant melanoma cells by targeting β3 integrin and the epithelial-mesenchymal transition

“…Luteolin (3',4',5,7-tetrahydroxyflavone), which is a common active flavonoid that is abundant in Lonicera japonica and Hedyotis diffusa, as well as in a vast and diverse array of other plants, has been widely used in the treatment of melanoma [12,23] . The antitumor effects of luteolin have been well documented in several different human cancers [24][25][26] ; furthermore, luteolin has been reported to elicit anti-EMT effects in cancer cell lines such as PC3 and A431 [27,28] . However, studies investigating the impact of luteolin on the invasion and migration of melanoma cells undergoing EMT and the signaling pathways associated with luteolin remain limited.…”