Trichothecin Induces Cell Death in NF-kB Constitutively Activated Human Cancer Cells via Inhibition of IKKb

Constitutive activation of the transcription factor nuclear factor-kB (NF-kB) is involved in tumorigenesis and chemo-resistance. As the key regulator of NF-kB, IKKb is a major therapeutic target for various cancers. Trichothecin (TCN) is a metabolite isolated from an endophytic fungus of the herbal plant Maytenus hookeri Loes. In this study, we evaluated the anti-tumor activity of TCN and found that TCN markedly inhibits the growth of cancer cells with constitutively activated NF-kB. TCN induces G0/G1 cell cycle arrest and apoptosis in cancer cells, activating pro-apoptotic proteins, including caspase-3,-8 and PARP-1, and decreasing the expression of anti-apoptotic proteins Bcl-2, Bcl-xL, and survivin. Reporter activity assay and target genes expression analysis illustrated that TCN works as a potent inhibitor of the NF-kB signaling pathway. TCN inhibits the phosphorylation and degradation of IkBa and blocks the nuclear translocation of p65, and thus inhibits the expression of NF-kB target genes XIAP, cyclin D1, and Bcl-xL. Though TCN does not directly interfere with IKKb kinase, it suppresses the phosphorylation of IKKb. Overexpression of constitutively activated IKKb aborted TCN induced cancer cell apoptosis, whereas knockdown of endogenous IKKb with siRNA sensitized cancer cells toward apoptosis induced by TCN. Moreover, TCN showed a markedly weaker effect on normal cells. These findings suggest that TCN may be a potentia