Zerumbone down-regulates chemokine receptor CXCR4 expression leading to inhibition of CXCL12-induced invasion of breast and pancreatic tumor cells.
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.
Sung
Bokyung
B
Department of Experimental Therapeutics, Cytokine Research Laboratory, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Jhurani
Sonia
S
Ahn
Kwang Seok
KS
Mastuo
Yoichi
Y
Yi
Tingfang
T
Guha
Sushovan
S
Liu
Mingyao
M
Aggarwal
Bharat B
BB
D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology*; D045744:Cell Line, Tumor; D054377:Chemokine CXCL12 / Q000037:antagonists & inhibitors* / Q000502:physiology; D047369:Chromatin Immunoprecipitation; D017931:DNA Primers; D015536:Down-Regulation / Q000187:drug effects*; D018734:Genes, erbB-2; D006801:Humans; D009361:Neoplasm Invasiveness; D010190:Pancreatic Neoplasms / Q000473:pathology*; D019718:Receptors, CXCR4 / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012717:Sesquiterpenes / Q000494:pharmacology*
D054377:Chemokine CXCL12; D017931:DNA Primers; D019718:Receptors, CXCR4; D012717:Sesquiterpenes; C403304:zerumbone