Luteolin-7-O-β-d-Glucoside Inhibits Cellular Energy Production Interacting with HEK2 in Keratinocytes

Abstract

Flavonoids have been demonstrated to affect the activity of many mammalian enzyme systems. Their functional phenolic groups are able to mediate antioxidant effects by scavenging free radicals. Molecules of this class have been found able to modulate the activity of kinases, phospholipase A2, cyclooxygenases, lipoxygenase, glutathione S-transferase, and many others. Recently, it has been demonstrated that luteolin, in the form of Luteolin-7-O-β-d-glucoside (LUT-7G) is able to induce the keratinocyte differentiation process in vitro. This flavonoid is able to counteract the proliferative effects of IL-22/IL6 pathway by the inhibition of STAT3 activity also in vivo in a psoriatic mouse model. Observations on energy metabolism changes of differentiating cells led us to perform a complete metabolomics analysis using human primary keratinocytes treated with LUT-7G. Our results show that LUT-7G, is not only able to impair the nuclear translocation of STAT3, but it also blocks the energy metabolism pathway, depressing the glycolytic and Krebs pathway by the inhibition of hexokinase 2 activity. These data confirm that LUT-7G can be proposed as a potential candidate for the treatment of inflammatory and proliferative diseases, but its role as a hexokinase 2 (HEK2) inhibitor opens new perspectives in nutritional science, and especially in cancer therapy, in which the inhibition of the Warburg effect could be relevant.

Anti-Inflammatory and Proliferative Properties of Luteolin-7-O-Glucoside

“…The results show that the scratch is profoundly delayed by the treatment with LUT-7G ( Figure 2 G) with respect to the control ( Figure 2 F) in which a complete closure of the scratch is already visible in the 16 h time point. This regulation on cell grow could be also the consequence of another effect of LUT-7G, since it is known that LUT-7G is able to block also glucose metabolism [ 13 ].…”

“…Since a direct link has been demonstrated between inflammatory diseases of the skin, associated with chronic inflammation such as psoriasis, with atherosclerosis, and of cardiovascular diseases [ 39 , 40 , 41 ], we also used a keratinocyte model, in which a psoriatic phenotype has been induced with IL-22 treatment [ 12 , 13 ]. Modulated genes have been analyzed using a wider array model (Biorad PCR panel, see Methods).…”

“…It has been demonstrated that the inhibition of this pathway by LUT-7G is obtained by the impairment of the nuclear translocation of STAT3 [ 12 ]. Moreover, LUT-7G has been shown to have a strong antioxidant effect in growing cells and also has important effects on cellular energy production [ 13 ]. Suppression of proinflammatory cytokine responses via targeting the JAK/STAT3 pathway and the possible reduction of lipid accumulation and oxidation could be useful as a potential therapeutic strategy in patients with a high cardiovascular risk [ 6 ].…”

Flavonoids Targeting HIF-1: Implications on Cancer Metabolism

“…In addition to GLUT, flavonoids also affect various enzyme systems, including HK. Luteolin-7- O -β-D-glucoside (LUT-7G), an HKII inhibitor, suppressed HKII and thereby repressed glycolytic pathway in the keratinocytes [ 166 ]. Quercetin inhibited glycolysis and proliferation of glycolysis-dependent hepatocellular carcinoma (SMMC-7721 and Bel-7402) cells by downregulating HKII; it also decreased HKII expression and restrained the growth of hepatocellular carcinoma xenografts in vivo [ 167 ].…”

Treatment with Luteolin Improves Lipopolysaccharide-Induced Periodontal Diseases in Rats

“…It was originally isolated from thyme, dandelion, and sage leaves but is also present in numerous foods, such as carrots, fennel, peppers, celery, and in officinal herbs like chamomile tea [ 17 ]. The attention to this compound is due to its multiple biological properties, especially to its antioxidant and anti-inflammatory effects, as evidenced by numerous scientific studies [ 18 , 19 ]; in many in vitro and in vivo models, Lut has been shown to inhibit several pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α), and to modulate nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway, thus demonstrating the ability of flavonoids to inhibit inflammatory processes [ 20 , 21 , 22 ].…”