Curcumin-induced suppression of cell proliferation correlates with down-regulation of cyclin D1 expression and CDK4-mediated retinoblastoma protein phosphorylation.
Cyclin D1 is a proto-oncogene that is overexpressed in many cancers including breast and prostate. It plays a role in cell proliferation through activation of cyclin-dependent kinases. Curcumin, a diferuloylmethane, is a chemopreventive agent known to inhibit the proliferation of several breast and prostate cancer cell lines. It is possible that the effect of curcumin is mediated through the regulation of cyclin D1. In the present report we show that inhibition of the proliferation of various prostate, breast and squamous cell carcinoma cell lines by curcumin correlated with the down-regulation of the expression of cyclin D1 protein. In comparison, the down-regulation by curcumin of cyclin D2 and cyclin D3 was found only in selective cell lines. The suppression of cyclin D1 by curcumin led to inhibition of CDK4-mediated phosphorylation of retinoblastoma protein. We found that curcumin-induced down-regulation of cyclin D1 was inhibited by lactacystin, an inhibitor of 26S proteosome, suggesting that curcumin represses cyclin D1 expression by promoting proteolysis. We found that curcumin also down-regulated mRNA expression, thus suggesting transcriptional regulation. Curcumin also inhibited the activity of the cyclin D1 promoter-dependent reporter gene expression. Overall our results suggest that curcumin down-regulates cyclin D1 expression through activation of both transcriptional and post-transcriptional mechanisms, and this may contribute to the antiproliferative effects of curcumin against various cell types.
Mukhopadhyay
Asok
A
Cytokine Research Laboratory, Department of Bioimmunotherapy, The University of Texas MD Anderson Cancer Center, Box 143, 1515 Holcombe Boulevard, Houston, Texas, TX 77030, USA.
Banerjee
Sanjeev
S
Stafford
Lewis Joe
LJ
Xia
Chunzhi
C
Liu
Mingyao
M
Aggarwal
Bharat B
BB
D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000494:pharmacology; D001483:Base Sequence; D002455:Cell Division / Q000187:drug effects*; D003474:Curcumin / Q000494:pharmacology*; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism*; D056742:Cyclin D2; D056743:Cyclin D3; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases / Q000378:metabolism*; D016213:Cyclins / Q000378:metabolism; D017931:DNA Primers; D015536:Down-Regulation / Q000187:drug effects*; D006801:Humans; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger / Q000235:genetics; D016160:Retinoblastoma Protein / Q000378:metabolism*; D014407:Tumor Cells, Cultured
C080336:CCND2 protein, human; C534696:CCND3 protein, human; D056742:Cyclin D2; D056743:Cyclin D3; D016213:Cyclins; D017931:DNA Primers; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D016160:Retinoblastoma Protein; C067713:lactacystin; D019938:Cyclin D1; C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases; D003474:Curcumin; D000111:Acetylcysteine