Although
metastasis accounts for >90% of
cancer-related deaths, no therapeutic that targets this process has yet been approved. Because the
chemokine receptor CXCR4 is one of the targets closely linked with
tumor metastasis, inhibitors of this receptor have the potential to abrogate
metastasis. In the current report, we demonstrate that
celastrol can downregulate the CXCR4 expression on
breast cancer MCF-7 cells stably transfected with HER2, an oncogene known to induce the
chemokine receptor. Downregulation of CXCR4 by the
triterpenoid was not cell type-specific as downregulation occurred in
colon cancer,
squamous cell carcinoma, and
pancreatic cancer cells. Decrease in CXCR4 expression was not due to proteolysis as neither
proteasome inhibitors nor lysosomal stabilization had any effect. Quantitative reverse transcription polymerase chain reaction analysis revealed that downregulation of CXCR4
messenger RNA (
mRNA) by
celastrol occurred at the translational level.
Chromatin immunoprecipitation analysis revealed regulation at the transcriptional level as well. Abrogation of the
chemokine receptor by
celastrol or by gene-silencing was accompanied by suppression of invasiveness of
colon cancer cells induced by CXCL12, the
ligand for CXCR4. This effect was not cell type-specific as
celastrol also abolished invasiveness of pancreatic
tumor cells, and this effect again correlated with the disappearance of both the CXCR4
mRNA and CXCR4
protein. Other
triterpenes, such as
withaferin A and
gedunin, which are known to inhibit Hsp90, did not downregulate CXCR4 expression, indicating that the effects were specific to
celastrol. Overall, these results show that
celastrol has potential in suppressing invasion and
metastasis of
cancer cells by down-modulation of CXCR4 expression.