Curcumin decreases cell proliferation rates through BTG2-mediated cyclin D1 down-regulation in U937 cells

Curcumin is a promising chemopreventive agent due to its multiple properties including anti-inflammation, induction of apoptosis and inhibition of signal cascades involving cell proliferation. It has been reported that curcumin-treated cells show decreased expression of cyclin D1, ultimately resulting in decreased cell growth rate. Thus, modulation of cell cycle regulatory proteins by curcumin has been suggested as one of the important mechanisms underlying its chemopreventive effects. However, the precise molecular mechanisms involving down-regulation of cyclin D1 by curcumin are not largely understood. In this study we investigated the mechanisms of cyclin D1 down-regulation by curcumin in U937 cells. Expressions of cyclin D1, particularly at protein and mRNA levels, were clearly decreased in curcumin-treated cells. The stability of cyclin D1 mRNA was not affected by curcumin treatment. Treatment of curcumin increased expression of BTG2 mRNA, a member of anti-proliferative gene family and a negative transcriptional regulator of cyclin D1. Furthermore, overexpression of BTG2 led to down-regulation of cyclin D1 mRNA expression in U937 cells. Nuclear translocation of p65 NF-κB is involved in the expression of cyclin D1 mRNA. Treatment of curcumin inhibited nuclear translocation of p65 NF-κB. Moreover, the expression of cyclin D1 mRNA was dramatically decreased after co-treatment curcumin with NF-κB inhibitors. The data presented here indicate that curcumin-induced down-regulation of cyclin D1 mRNA is mediated by induction of BTG2 as well as inhibition of nuclear translocation of NF-κB.