Zerumbone Down-regulates Chemokine Receptor CXCR4 Expression Leading to Inhibition of CXCL12-Induced Invasion of Breast and Pancreatic Tumor Cells

Abstract

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-KB 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, A-humulene, which lacks the carbonyl group, was found to be inactive in inducing CXCR4 downregulation. Overall, our results show that zerumbone is a novel inhibitor of CXCR4 expression and thus has a potential in the suppression of cancer metastasis. [Cancer Res 2008;68(21):8938-44]

Chemokine receptors in gastric MALT lymphoma: loss of CXCR4 and upregulation of CXCR7 is associated with progression to diffuse large B-cell lymphoma

“…Additionally, CXCR7 expression was associated with the proliferation rate of gastric MALT lymphomas and extranodal diffuse large B-cell lymphoma in our study. CXCL12-the ligand of CXCR4 and CXCR7 20-22 -has been linked to multiple key processes in tumor cells, including proliferation, survival, migration, invasion and metastasis in more than 20 different types of cancer, [42][43][44][45][46][47][48][49] providing evidence for the importance of this chemokine signaling pathway in cancer. CXCR7 expression was described in malignant cell types, in fetal liver cells and on tumor-associated blood vessels but not in normal vessels.…”

PAUF functions in the metastasis of human pancreatic cancer cells and upregulates CXCR4 expression

“…In line with these previous reports, our immunohistochemical results indicate CXCR4 expression in pancreatic tumor tissues. CXCR4 expression increases metastatic potential of pancreatic cancer cells in vivo, resulting in liver and lung metastasis in a mouse model (Saur et al, 2005), whereas CXCR4-specific shRNA or zerumbone, a compound that negatively regulates CXCR4 expression, inhibits pancreatic cancer cell invasion (Sung et al, 2008;Wang et al, 2008). Furthermore, it is suggested that a subpopulation of migrating CD133 þ CXCR4 þ pancreatic cancer stem cells is essential for tumor metastasis (Hermann et al, 2007).…”

Key cell signaling pathways modulated by zerumbone: Role in the prevention and treatment of cancer

“…Aggarwal and co-workers also reported the potential suppressive effects of zerumbone on the chemokine receptor CXCR4 [51], which is found to be overexpressed in several tumors [52]. Zerumbone suppressed both human epidermal growth factor receptor 2 (HER2)-induced CXCR4 expression in MCF7 breast cancer cell lines and constitutive CXCR4 expression in a variety of cancer cell lines such as leukemia (KBM-5), myeloma (U266), head and neck squamous cell carcinomas (SCC4), kidney carcinoma (A293), lung adenocarcinoma (H1299) and pancreatic carcinoma (PANC-1, PANC-28 and MIA PaCa-2).…”