Constitutive activation of the
transcription factor nuclear factor-κB (NF-κB) is involved in
tumorigenesis and chemo-resistance. As the key regulator of NF-κB, IKKβ 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-κB. 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-κB signaling pathway. TCN inhibits the phosphorylation and degradation of IκBα and blocks the nuclear translocation of p65, and thus inhibits the expression of NF-κB target genes XIAP,
cyclin D1, and Bcl-xL. Though TCN does not directly interfere with IKKβ
kinase, it suppresses the phosphorylation of IKKβ. Overexpression of constitutively activated IKKβ aborted TCN induced
cancer cell apoptosis, whereas knockdown of endogenous IKKβ 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 potential therapeutic candidate for
cancer treatment, targeting NF-κB signaling.