(E)‐2,4‐bis(p‐hydroxyphenyl)‐2‐butenal has an antiproliferative effect on NSCLC cells induced by p38 MAPK‐mediated suppression of NF‐κB and up‐regulation of TNFRSF10B (DR5)

Abstract

BACKGROUND AND PURPOSEThe Maillard Reaction Products (MRPs) are known to be effective in chemoprevention. Here we focused on the anticancer effects of (E)-2,4-bis(p-hydroxyphenyl)-2-butenal (a MRP) on human non-small-cell lung cancer (NSCLC) cells and its mechanism of action. EXPERIMENTAL APPROACHWe analysed the activity of (E)-2,4-bis(p-hydroxyphenyl)-2-butenal on NSCLC cells (NCI-H460 and A549) by use of Western blot analysis for major apoptotic proteins, MAPK, NF-kB and death receptor expression. We also used RT-PCR to determine its effects on death receptor mRNA expression, EMSA for effects on NF-kB DNA binding activity and colony formation assay for effects of inhibitors on (E)-2,4-bis(p-hydroxyphenyl)-2-butenal's actions. KEY RESULTS(E)-2,4-bis(p-hydroxyphenyl)-2-butenal induced a concentration (10-40 mg·mL -1 )-and time (30 min-72 h)-dependent inhibitory effect on the growth of NSCLC cells due to induction of apoptosis. Concomitantly, it significantly increased the expression of apoptotic proteins such as cleaved caspase-3, cleaved caspase-9, Bax and p53, but down-regulated the expression of anti-apoptotic proteins Bcl-2, cIAP1 and cIAP2. This effect was induced by up-regulation of MAPK and death receptor proteins TNFRSF12, TNFRSF10B and TNFRSF21, but suppression of NF-kB. Of the death receptors activated, only TNFRSF10B knock down with siRNA reversed the effect of (E)-2,4-bis(p-hydroxyphenyl)-2-butenal. Even though all the MAPKs were activated, only pretreatment with a p38 MAPK inhibitor reversed (E)-2,4-bis(p-hydroxyphenyl)-2-butenal-induced cell growth inhibition, increase in cleaved caspase-3, -9 and TNFRSF10B expression, and NF-kB inactivation. CONCLUSIONS AND IMPLICATIONS(E)-2,4-bis(p-hydroxyphenyl)-2-butenal induces apoptosis in NSCLC cells by p38 MAPK-mediated suppression of NF-kB and activation of TNFRSF10B, which then activates the caspase-3 and caspase-9 pathways. AbbreviationsNSCLC, non small cell lung cancer BJP British Journal of Pharmacology

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