Evodiamine Abolishes Constitutive and Inducible NF-κB Activation by Inhibiting IκBα Kinase Activation, Thereby Suppressing NF-κB-regulated Antiapoptotic and Metastatic Gene Expression, Up-regulating Apoptosis, and Inhibiting Invasion

Abstract

Evodiamine, an alkaloidal component extracted from the fruit of Evodiae fructus (Evodia rutaecarpa Benth., Rutaceae), exhibits antiproliferative, antimetastatic, and apoptotic activities through a poorly defined mechanism. Because several genes that regulate cellular proliferation, carcinogenesis, metastasis, and survival are regulated by nuclear factor-B (NF-B), we postulated that evodiamine mediates its activity by modulating NF-B activation. In the present study, we investigated the effect of evodiamine on NF-B and NF-B-regulated gene expression activated by various carcinogens. We demonstrate that evodiamine was a highly potent inhibitor of NF-B activation, and it abrogated both inducible and constitutive NF-B activation. The inhibition corresponded with the sequential suppression of IB␣ kinase activity, IB␣ phosphorylation, IB␣ degradation, p65 phosphorylation, p65 nuclear translocation, and p65 acetylation. Evodiamine also inhibited tumor necrosis factor (TNF)-induced Akt activation and its association with IKK. Suppression of Akt activation was specific, because it had no effect on JNK or p38 MAPK activation.

Evodiamine induces apoptosis in pancreatic carcinoma PANC-1 cells via NF κB inhibition

“…We found that evodiamine induced apoptotic cell death in PANC-1 cells dose-dependently. The results are in line with previous reports that evodiamine inhibits growth and induces apoptosis in various cancer cell lines of different origin (Kan et al, 2004;Lee et al, 2011;Takada et al, 2005;Yang et al, 2009;Zhang et al, 2004).…”

“…The results showed that evodiamine significantly inhibited the expression of NF-κBp65 in nuclear extract in a dosedependent manner. The results are further supported by a previous study by Takada et al (2005) who found a similar inhibitory effect of evodiamine on constitutive and inducible NF-κB activation in lung adenocarcinoma, T-cell lymphoma and multiple myeloma.…”

“…Evodiamine is one of the main components of Evodiae fructus (Takada et al, 2005). It has been shown to exhibit anti-cancer activities against various cancer cell lines including human malignant melanoma, breast cancer (Zhang et al, 2004), cervical cancer (Yang et al, 2008), colorectal cancer (Yang et al, 2009), lung cancer (Takada et al, 2005), prostate cancer (Kan et al, 2004) and leukemia (Lee et al, 2011) through different mechanisms. However, the anti-cancer effect and molecular mechanism of evodiamine on pancreatic cancer remain largely unknown.…”

Constitutively Activated Nuclear Factor-κB, but not Induced NF-κB, Leads to TRAIL Resistance by Up-Regulation of X-Linked Inhibitor of Apoptosis Protein in Human Cancer Cells

“…Hence, to fully predict tumor responses, both antiapoptotic and proapoptotic programs have to be assessed. Nevertheless, constitutively activated NF-nB is a common feature in tumors (62,(89)(90)(91)(92)(93), and activated NF-nB has been implicated in carcinogenesis, metastasis, and chemoresistance (92,(94)(95)(96)(97). Because NF-nB activation has been associated with resistance to many anticancer drugs, targeting NF-nB to improve the outcome of cancer therapy has been frequently suggested.…”

Proteasome inhibition induces hepatic stellate cell apoptosis

“…NF-B induces expression of survival genes, including the anti-apoptotic Bcl-2 family proteins Bcl-xL and A1 12 ; loss of these proteins can result in cell death. 13 Proteasome inhibition prevents I-B degradation, blocking NF-B activation, an effect which can culminate in loss of survival proteins and cell death. 14 In addition to blocking NF-B activation, proteasome inhibitors may also upregulate death receptor 5 (DR5) and the proapoptotic BH3-only protein, Bim.…”