Caffeine inhibits UV-mediated NF-κB activation in A2058 melanoma cells: an ATM-PKCδ-p38 MAPK-dependent mechanism

Abstract

Mammalian ultraviolet (UV) radiation response is a gene induction cascade activated by several transcription factors, including NF-kappaB. Although NF-kappaB is induced by UV radiation, the signal transduction mechanism remains relatively unclear. In the present study, we show that UV-induced NF-kappaB activation is mediated by the activation of Ataxia telangiecia mutated (ATM) and protein kinase C (PKC). We also show that caffeine specifically inhibits UV-mediated NF-kappaB activation, but not TNFalpha-mediated NF-kappaB activation. In addition, our study shows that ATM, but not ATM-Rad3-related (ATR) or DNA-dependent protein kinase (DNA-PK) is involved in UV-induced NF-kappaB activation. Because SB203580 (a p38 MAPK inhibitor), or Calphostin C or rottlerin (PKC inhibitors) was able to inhibit UV-mediated NF-kappaB activation, we evaluated whether caffeine could inhibit p38 MAPK or PKC activity. Caffeine or rottlerin inhibited UV-induced phosphorylation of p38 MAPK, but not anisomycin-induced phosphorylation of p38 MAPK, suggesting that p38 MAPK is downstream of PKC. Additionally, caffeine could effectively inhibit UV-induced increases in PKC activity. Taken together, our study demonstrates that caffeine is a potent inhibitor of UV-induced NF-kappaB activation. Additionally, this inhibition occurs due to the inhibitory action of caffeine on ATM and PKC, resulting in the inhibition of p38 MAPK activation.

NF-κB-dependent MicroRNA-125b Up-regulation Promotes Cell Survival by Targeting p38α upon Ultraviolet Radiation

“…Previous study implicated that ATM may be involved in regulating NF-B signaling in UV-treated melanoma cells (38). Using pharmacological and genetic approaches, we demonstrated that ATM is indispensable for NF-B activation by UV treatment, which is conserved among different cell types and between species.…”

Caffeine and Caffeic Acid Inhibit Growth and Modify Estrogen Receptor and Insulin-like Growth Factor I Receptor Levels in Human Breast Cancer

“…Caffeine has also been shown to inhibit skin cancer in mice by enhancing UVB-induced apoptosis (35). The experimental doses used in the present study are equivalent to previous in vitro studies (30)(31)(32)(33), although the higher doses are above the physiologic achievable systemic doses. Translating experimental in vitro doses to human in vivo settings frequently requires significant dose adjustments due to pharmacokinetic and pharmacodynamic parameters along with differences in acute in vitro exposure versus cumulative effects following long-term exposure.…”

“…The shifted ER proportions are in line with both the clinical and experimental data in the present study. Several studies have described caffeine and caffeic acid as anticarcinogenic agents in various cell culture and in vivo models (30,31). For instance, in hepatocellular carcinoma and epidermal JB6 cells, caffeine attenuated cell growth via induction of G 0 -G 1 cell-cycle arrest (32,33).…”

Perturbations in Ataxia Telangiectasia Mutant Signaling Pathways After Drug-Induced Acute Liver Failure and Their Reversal During Rescue of Animals by Cell Therapy

“…26 Similarly, Atm deficiency amplified genotoxicity induced by Phen. 27 Also, inhibition of Atm expression by caffeine, a well-characterized ATM kinase inhibitor, 28 significantly increased APAP hepatotoxicity. 29 Because expression of Atm is largely governed by promoter regulation, 30 and is negatively regulated by displacement of positive transcriptional transactivators with soluble factors (eg, epidermal growth factor or hepatocyte growth factor), 31,32 it should be reasonable to consider whether soluble factors will be relevant in DILI and Atm expression and in improvement of Atm expression after cell therapy.…”