CXC chemokine receptor 4 (CXCR4), initially linked with leukocyte trafficking, is now known to be expressed in various
tumors including breast, ovary, prostate, gastrointestinal, head and neck, bladder, brain, and
melanoma. This receptor mediates homing of
tumor cells to specific organs that express the
ligand CXCL12 for this receptor. Thus, agents that can down-regulate CXCR4 expression have potential against
cancer metastasis. In this study, we report the identification of
zerumbone, a component of subtropical ginger (Zingiber zerumbet), as a regulator of CXCR4 expression. This
sesquiterpene down-regulated the expression of CXCR4 on HER2-overexpressing
breast cancer cells in a dose- and time-dependent manner. The decrease in CXCR4 by
zerumbone was found to be not cell type specific as its expression was abrogated in leukemic, skin, kidney, lung, and
pancreatic cancer cell lines. The down-regulation of CXCR4 was not due to proteolytic degradation but rather to transcriptional regulation, as indicated by down-regulation of
mRNA expression, inhibition of
nuclear factor-kappaB activity, and suppression of
chromatin immunoprecipitation activity. Suppression of CXCR4 expression by
zerumbone correlated with the inhibition of CXCL12-induced invasion of both breast and
pancreatic cancer cells. An analogue of
zerumbone,
alpha-humulene, which lacks the carbonyl group, was found to be inactive in inducing CXCR4 down-regulation. Overall, our results show that
zerumbone is a novel inhibitor of CXCR4 expression and thus has a potential in the suppression of
cancer metastasis.