Open AccessDigitoflavone Inhibits IκBα Kinase and Enhances Apoptosis Induced by TNFα through Downregulation of Expression of Nuclear Factor κB-Regulated Gene Products in Human Pancreatic Cancer Cells
Author(s) -
Xueting Cai,
Wei Lü,
Yang Yang,
Jie Yang,
Juan Ye,
Gu Z,
Chunping Hu,
Xiaoning Wang,
Peng Cao
Publication year - 2013
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0077126
Subject(s) - iκb kinase , survivin , tumor necrosis factor alpha , cancer research , iκbα , nfkb1 , kinase , biology , apoptosis , transcription factor , nf κb , signal transduction , cyclin d1 , microbiology and biotechnology , chemistry , cell cycle , biochemistry , immunology , gene
Tumor necrosis factor-α (TNFα) activates both cell death and cell survival pathways. The activation of survival pathway renders most cancer cells resistant to TNF-induced cytotoxicity. We found that pretreatment with digitoflavone, a plant flavonoid, greatly sensitized TNFα-induced apoptotic cell death in several human pancreatic cancer cells. In search of the molecular basis of the sensitization effect of digitoflavone, digitoflavone was found to inhibit TNFα-induced activation of nuclear transcription factor-kappa B (NF-κB) which is the main survival factor in TNFα signaling. NF-κB suppression occurred through inhibition of IκBα kinase activation, IκBα phosphorylation, IκBα degradation, and NF-κB nuclear translocation. This inhibition correlated with suppression of NF-κB-dependent genes involved in antiapoptosis (mcl-1, bcl-2, bcl-xl, c-iap1, c-iap2, flip, and survivin), proliferation (c-myc, cyclin d1), and angiogenesis (vegf, cox-2, and mmp-9). In addition, digitoflavone can activate JNK through inhibition of NF-κB signaling, provide a continuous blockade of the feed-back inhibitory mechanism by JNK-induced NF-κB activation. This study found a novel function of digitoflavone and enhanced the value of digitoflavone as an anticancer agent.