Sesquiterpene Lactone Bigelovin Induces Apoptosis Of Colon Cancer Cells Through Inducing Ikk-Beta Degradation And Suppressing Nuclear Factor Kappa B Activation

Bigelovin, a sesquiterpene lactone extracted from plant Inula helianthus aquatica, exhibited multiple interesting biological activities, including anti-inflammation, antiangiogenesis and cytotoxic action against cancer cells. In the present study, we found that Bigelovin reduced the viability of human colon cancer cells and induced their apoptosis in a time- and dose-dependent manner, with an IC50-5 mu M. RNAseq and luciferase reporter analyses revealed that the nuclear factor kappa B (NF-kappa B) signaling was one of the most significantly inhibited pathways after Bigelovin treatment. Further systemic examination showed that exposure to Bigelovin resulted in ubiquitination and degradation of inhibitor of kappa-B kinase-beta (IKK-beta) and decrease of I kappa B-alpha and p65 phosphorylation, which led to the downregulation of NF-kappa B-regulated genes expression. Moreover, enforced expression of exogenous IKK-beta attenuated Bigelovin-induced NF-kappa B suppression and cell viability reduction. These results indicated that Bigelovin exerts a cytotoxic action against colon cancer cells through the induction of IKK-beta degradation and consequently the inhibition of NF-kappa B signaling. Given the abnormal activation of NF-kappa B signaling in colorectal cancer (CRC) cells and the critical role of chronic inflammation in CRC development, it is conceivable that at least some colorectal cancer cells are addictive to NF-kappa B activation and targeting the pathway is an effective anti-CRC strategy.