Curcumin induces the degradation of cyclin E expression through ubiquitin-dependent pathway and up-regulates cyclin-dependent kinase inhibitors p21 and p27 in multiple human tumor cell lines.
Curcumin, a well-known chemopreventive agent, has been shown to suppress the proliferation of a wide variety of tumor cells through a mechanism that is not fully understood. Cyclin E, a proto-oncogene that is overexpressed in many human cancers, mediates the G(1) to S transition, is a potential target of curcumin. We demonstrate in this report a dose- and time-dependent down-regulation of expression of cyclin E by curcumin that correlates with the decrease in the proliferation of human prostate and breast cancer cells. The suppression of cyclin E expression was not cell type dependent as down-regulation occurred in estrogen-positive and -negative breast cancer cells, androgen-dependent and -independent prostate cancer cells, leukemia and lymphoma cells, head and neck carcinoma cells, and lung cancer cells. Curcumin-induced down-regulation of cyclin E was reversed by proteasome inhibitors, lactacystin and N-acetyl-L-leucyl-L-leucyl-L-norleucinal, suggesting the role of ubiquitin-dependent proteasomal pathway. We found that curcumin enhanced the expression of tumor cyclin-dependent kinase (CDK) inhibitors p21 and p27 as well as tumor suppressor protein p53 but suppressed the expression of retinoblastoma protein. Curcumin also induced the accumulation of the cells in G1 phase of the cell cycle. Overall, our results suggest that proteasome-mediated down-regulation of cyclin E and up-regulation of CDK inhibitors may contribute to the antiproliferative effects of curcumin against various tumors.
Aggarwal
Bharat B
BB
Cytokine Research Laboratory, Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA. aggarwal@mdanderson.org
Banerjee
Sanjeev
S
Bharadwaj
Uddalak
U
Sung
Bokyung
B
Shishodia
Shishir
S
Sethi
Gautam
G
D045744:Cell Line, Tumor; D003474:Curcumin / Q000494:pharmacology*; D019927:Cyclin E / Q000378:metabolism*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism*; D006801:Humans; D008297:Male; D009369:Neoplasms / Q000473:pathology; D015513:Oncogene Proteins / Q000378:metabolism*; D000090063:Proto-Oncogene Mas; D025801:Ubiquitin / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
C475820:CCNE1 protein, human; D019927:Cyclin E; D050759:Cyclin-Dependent Kinase Inhibitor p21; C000715470:MAS1 protein, human; D015513:Oncogene Proteins; D000090063:Proto-Oncogene Mas; D025801:Ubiquitin; D050760:Cyclin-Dependent Kinase Inhibitor p27; D003474:Curcumin