Curcumin Selectively Induces Apoptosis in Deregulated Cyclin D1-expressed Cells at G2Phase of Cell Cycle in a p53-dependent Manner

Tathagata Choudhuri, Suman Pal, Tanya Das, Gaurisankar Sa
2005 Journal of Biological Chemistry  
Curcumin (diferuloylmethane) is known to induce apoptosis in tumor cells. In asynchronous cultures, with time-lapse video-micrography in combination with quantitative fluorescence microscopy, we have demonstrated that curcumin induces apoptosis at G 2 phase of cell cycle in deregulated cyclin D1-expressed mammary epithelial carcinoma cells, leaving its normal counterpart unaffected. In our search toward delineating the molecular mechanisms behind such differential activities of curcumin, we
more » ... of curcumin, we found that it selectively increases p53 expression at G 2 phase of carcinoma cells and releases cytochrome c from mitochondria, which is an essential requirement for apoptosis. Further experiments using p53-null as well as dominant-negative and wildtype p53-transfected cells have established that curcumin induces apoptosis in carcinoma cells via a p53dependent pathway. On the other hand, curcumin reversibly inhibits normal mammary epithelial cell cycle progression by down-regulating cyclin D1 expression and blocking its association with Cdk4/Cdk6 as well as by inhibiting phosphorylation and inactivation of retinoblastoma protein. In addition, curcumin significantly up-regulates cell cycle inhibitory protein (p21Waf-1) in normal cells and arrests them in G 0 phase of cell cycle. Therefore, these cells escape from curcumin-induced apoptosis at G 2 phase. Interestingly, these processes remain unaffected by curcumin in carcinoma cells where cyclin D1 expression is high. Similarly, in ectopically overexpressed system, curcumin cannot down-regulate cyclin D1 and thus block cell cycle progression. Hence, these cells progress into G 2 phase and undergo apoptosis. These observations together suggest that curcumin may have a possible therapeutic potential in breast cancer patients.
doi:10.1074/jbc.m410670200 pmid:15738001 fatcat:6fgadpqq2fdg7fhwaiiq4rfa7u