Gene-expression profiling during curcumin-induced apoptosis reveals downregulation of CXCR4.
OBJECTIVE
A dietary compound curcumin hardwires to multiple cellular processes, with suppression of cell proliferation, induction of apoptosis, and inhibition of metastasis considered as the major mechanisms underlying its anticancer properties. Based on our recent evidence that curcumin triggers cell demise in follicular lymphoma (FL) cells, we aimed to identify curcumin-regulated genes of utmost importance for the treatment of follicular lymphoma.


METHODS
Large-scale gene-expression profiling was performed during curcumin-triggered apoptosis (8-36 hours) in follicular lymphoma HF4.9 cells using Sentrix Human WG-6 BeadChips. Expression levels of selected differentially expressed genes were verified by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) and immunoblotting. Chemical inhibitor studies (cyclosporin A and AMD3100) were performed to provide further insights into the functional significance of selected genes.


RESULTS
Comprehensive transcriptional response is associated with curcumin treatment in HF4.9 cells, including differential expression of genes encoding apoptotic signaling proteins, tumor and metastasis suppressors, transcription and splicing factors, proteins involved in regulation of cell adhesion, migration (e.g., CXCR4), lymphoid development, or B-cell activation (e.g. CD20), and others. CXCR4 downregulation was confirmed by both qRT-PCR and immunoblotting. Importantly, curcumin induced downregulation of CXCR4 protein also in other FL cell lines, and similar effect was observed upon prolonged incubation with low concentration of curcumin. AMD3100 (a selective CXCR4 antagonist) alone enhanced neither spontaneous nor serum-starvation-induced death at 24 hours of treatment, but impaired long-term cell growth in a cell line-dependent fashion.


CONCLUSIONS
To our knowledge this is the first study showing curcumin-induced downregulation of CXCR4, and at attainable in vivo concentration of the polyphenol. Other curcumin-regulated genes identified herein, e.g., CD20, are also seemingly pertinent to the pathophysiology of follicular lymphoma.
Skommer
Joanna
J
Department of Clinical Sciences, University of Kuopio, Kuopio, Finland. joannaskommer@yahoo.com
Wlodkowic
Donald
D
Pelkonen
Jukka
J
D018951:Antigens, CD20 / Q000187:drug effects / Q000235:genetics; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D003474:Curcumin / Q000494:pharmacology*; D015536:Down-Regulation / Q000235:genetics*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008224:Lymphoma, Follicular / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D019718:Receptors, CXCR4 / Q000187:drug effects / Q000235:genetics*
D018951:Antigens, CD20; D019718:Receptors, CXCR4; D003474:Curcumin