Previously, we reported that
retigeric acid B (RB), a natural pentacyclic triterpenic
acid isolated from lichen, inhibited cell growth and induced apoptosis in
androgen-independent
prostate cancer (PCa) cells. However, the mechanism of action of RB remains unclear. In this study, we found that using PC3 and DU145 cells as models, RB inhibited phosphorylation levels of IκBα and p65 subunit of NF-κB in a time- and dosage-dependent manner. Detailed study revealed that RB blocked the nuclear translocation of p65 and its
DNA binding activity, which correlated with suppression of NF-κB-regulated
proteins including Bcl-2, Bcl-x(L),
cyclin D1 and
survivin. NF-κB reporter assay suggested that RB was able to inhibit both constitutive activated-NF-κB and LPS (
lipopolysaccharide)-induced activation of NF-κB. Overexpression of RelA/p65 rescued RB-induced cell death, while knockdown of RelA/p65 significantly promoted RB-mediated inhibitory effect on cell proliferation, suggesting the crucial involvement of NF-κB pathway in this event. We further analyzed antitumor activity of RB in in vivo study. In C57BL/6 mice carrying RM-1 homografts, RB inhibited
tumor growth and triggered apoptosis mainly through suppressing NF-κB activity in
tumor tissues. Additionally,
DNA microarray data revealed global changes in the gene expression associated with cell proliferation, apoptosis, invasion and
metastasis in response to RB treatment. Therefore, our findings suggested that RB exerted its anti-
tumor effect by targeting the NF-κB pathway in PCa cells, and this could be a general mechanism for the anti-
tumor effect of RB in other types of
cancers as well.