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( E )‐2,4‐bis( p ‐hydroxyphenyl)‐2‐butenal has an antiproliferative effect on NSCLC cells induced by p38 MAPK ‐mediated suppression of NF ‐κ B and up‐regulation of TNFRSF10B (DR5)
Author(s) -
Kollipara Pushpa Saranya,
Jeong Heon Sang,
Han Sang Bae,
Hong Jin Tae
Publication year - 2013
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.12024
Subject(s) - mapk/erk pathway , p38 mitogen activated protein kinases , chemistry , microbiology and biotechnology , pharmacology , phosphorylation , biology , biochemistry
Background And Purpose The M aillard R eaction P roducts ( 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 Approach We analysed the activity of ( E )‐2,4‐bis( p ‐hydroxyphenyl)‐2‐butenal on NSCLC cells ( NCI ‐ H 460 and A 549) by use of Western blot analysis for major apoptotic proteins, MAPK , NF‐ κ B and death receptor expression. We also used RT‐PCR to determine its effects on death receptor mRNA expression, EMSA for effects on NF‐ κ B 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 μg·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, B ax and p53, but down‐regulated the expression of anti‐apoptotic proteins B cl‐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‐ κ B . 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 MAPK s 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‐ κ B inactivation. Conclusions And Implications ( E )‐2,4‐bis( p ‐hydroxyphenyl)‐2‐butenal induces apoptosis in NSCLC cells by p38 MAPK‐mediated suppression of NF‐κB and activation of TNFRSF10B, which then activates the caspase‐3 and caspase‐9 pathways.