Received for publication July 12, 2006.
Revised October 4, 2006.
Accepted for publication October 5, 2006.

Embelin, an Inhibitor of XIAP, Blocks Nuclear Factor-B (NF-B) Signaling Pathway Leading to Suppression of NF-B-regulated Anti-apoptotic and Metastatic Gene Products

Abstract

Identifying the active chemical ingredients of ancient medicines and the molecular targets of those ingredients is an attractive therapeutic objective. Embelin, identified primarily from the Embelia ribes plant, is one such compound shown to exhibit chemopreventive, anti-inflammatory, and apoptotic activities through an unknown mechanism. Because nuclear factor-B (NF-B) regulates several genes associated with inflammation, proliferation, carcinogenesis, and apoptosis, we postulated that embelin might mediate its activity through modulation of NF-B activation. We found that embelin inhibited tumor necrosis factor (TNF)-induced NF-B activation. Both inducible and constitutive NF-B activation was abrogated by embelin. In addition, NF-B activated by diverse stimuli such as interleukin-1, lipopolysaccharide, phorbol myristate acetate, okadaic acid, hydrogen peroxide, and cigarette smoke condensate also suppressed. We found that embelin inhibited sequentially the TNF-induced activation of the inhibitory subunit of NF-B (IB) kinase, IB phosphorylation, IB degradation, and p65 phosphorylation and nuclear translocation. Embelin also suppressed NF-B-dependent reporter gene transcription induced by TNF, TNF receptor-1 (TNFR1), TNFR1-associated death domain protein, TNFR-associated factor-2, NF-B-inducing kinase, and IB kinase but not by p65. Further, we found that embelin down-regulated gene products involved in cell survival, proliferation, invasion, and metastasis of the tumor. This down-regulation was associated with enhanced apoptosis by cytokines and chemotherapeutic agents. Taken together, our results indicate that embelin is a novel NF-B blocker and potential suppressor of tumorigenesis.

Key words: Tumor necrosis factor, NFkappaB, Mechanisms of cell killing/apoptosis

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