A polyphenol mixture from cinnamon targets p38 MAP kinase-regulated signaling pathways to produce G2/M arrest.
We recently demonstrated that treatment of three leukemic cell lines with an aqueous extract of cinnamon (CE) for 24 h produced dose-dependent arrests in the G2/M phase of the cell cycle. To accomplish the goal of understanding underlying mechanisms, we selected the cell line most responsive to the CE treatment to study the effects of the extract on signaling molecules regulating cell cycle progression. Cell cycle analyses were conducted on treated versus nontreated cells from 0-6 h. The percentages of cells in G2/M in CE-treated cells increased significantly from 11.0+/-1.0 to 23.6+/-1.4 after 6 h, while the percentage for nontreated cells remained unchanged (12.3+/-0.8). Multiparametric flow cytometric analyses were used to associate activation of p38 mitogen-activated protein kinase (MAPK) with cells arrested in G2/M, the size of these cells, and the presence or absence of cyclin B1. After 4 h, there was a 26% increase in the activated phosphorylated form of p38 MAPK in CE-treated cells compared with the nontreated control cells, with larger cells showing the greater increases. Although the proportion of CE-treated cells in G2/M was higher than controls, this population was shown to be less positive for cyclin B1 than the control G2/M population. Our results demonstrate that CE significantly modulated two signaling proteins, p38 MAPK and cyclin B, that regulate progression through G2/M. Overall, the data provide evidence that CE affects proliferation in a leukemic cell line by disrupting critical phosphorylating/dephosphorylating signaling events that propel cells through the G2/M phase.
Schoene
Norberta W
NW
Diet, Genomics, and Immunology Laboratory, Beltsville Human Nutrition Research Center, ARS, USDA, Beltsville, MD 20705-2350, USA. norberta.schoene@ars.usda.gov
Kelly
Meghan A
MA
Polansky
Marilyn M
MM
Anderson
Richard A
RA
D002453:Cell Cycle / Q000187:drug effects*; D048429:Cell Size / Q000187:drug effects; D002935:Cinnamomum zeylanicum; D002999:Clone Cells; D019926:Cyclin B / Q000187:drug effects / Q000235:genetics; D056744:Cyclin B1; D005419:Flavonoids / Q000494:pharmacology*; D005434:Flow Cytometry / Q000379:methods; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D019169:Jurkat Cells; D017493:Leukocyte Common Antigens / Q000172:deficiency; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D010636:Phenols / Q000494:pharmacology*; D010936:Plant Extracts / Q000494:pharmacology; D059808:Polyphenols; D014407:Tumor Cells, Cultured; D048051:p38 Mitogen-Activated Protein Kinases / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism
C534699:CCNB1 protein, human; D019926:Cyclin B; D056744:Cyclin B1; D005419:Flavonoids; D010636:Phenols; D010936:Plant Extracts; D059808:Polyphenols; D048051:p38 Mitogen-Activated Protein Kinases; D017493:Leukocyte Common Antigens