Ninety percent of
cancer-mediated deaths are due to
metastasis of the
tumor; however, the mechanisms controlling
metastasis remain poorly understood. Thus, no
therapy targeting this process has yet been approved.
Chemokines and their receptors are mediators of chronic
inflammation and have been linked to the
metastasis of numerous
cancers. More recently, the
Cysteine X
Cysteine (
CXC) chemokine receptor 4 (CXCR4) has emerged as a key mediator of
tumor metastasis; therefore, identification of inhibitors of this receptor has the potential to abrogate
metastasis. In this report, we demonstrate that acetyl-11-keto-β-boswellic
acid (AKBA), a component of the therapeutic plant Boswellia serrata, can downregulate CXCR4 expression in
pancreatic cancer cells. The reduction in CXCR4 induced by this
terpenoid was found to be cell-type specific, as its expression was also abrogated in
leukemia, myeloma and
breast cancer cell lines. Neither
proteasome inhibitors nor lysosomal stabilization could prevent the AKBA-induced reduction in CXCR4 expression. This downregulation occurred at the transcriptional level. Suppression of CXCR4 by AKBA was accompanied by the inhibition of
pancreatic cancer cell invasion, which is induced by CXCL12, the
ligand for CXCR4. In addition, abrogation of the expression of
chemokine receptor by AKBA was found in human pancreatic tissues from orthotopic animal model. AKBA also abolished
breast tumor cell invasion, and this effect correlated with the disappearance of both the CXCR4
messenger RNA and CXCR4
protein. Overall, our results show that AKBA is a novel inhibitor of CXCR4 expression and, thus, has the potential to suppress the invasion and
metastasis of
cancer cells.