Abstract
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.