title: Anaphase-promoting complex/cyclosome protein Cdc27 is a target for curcumin-induced cell cycle arrest and apoptosis.
abstract: BACKGROUND
  Curcumin (diferuloylmethane), the yellow pigment in the Asian spice turmeric, is a hydrophobic polyphenol from the rhizome of Curcuma longa. Because of its chemopreventive and chemotherapeutic potential with no discernable side effects, it has become one of the major natural agents being developed for cancer therapy. Accumulating evidence suggests that curcumin induces cell death through activation of apoptotic pathways and inhibition of cell growth and proliferation. The mitotic checkpoint, or spindle assembly checkpoint (SAC), is the major cell cycle control mechanism to delay the onset of anaphase during mitosis. One of the key regulators of the SAC is the anaphase promoting complex/cyclosome (APC/C) which ubiquitinates cyclin B and securin and targets them for proteolysis. Because APC/C not only ensures cell cycle arrest upon spindle disruption but also promotes cell death in response to prolonged mitotic arrest, it has become an attractive drug target in cancer therapy.
  
  
  METHODS
  Cell cycle profiles were determined in control and curcumin-treated medulloblastoma and various other cancer cell lines. Pull-down assays were used to confirm curcumin binding. APC/C activity was determined using an in vitro APC activity assay.
  
  
  RESULTS
  We identified Cdc27/APC3, a component of the APC/C, as a novel molecular target of curcumin and showed that curcumin binds to and crosslinks Cdc27 to affect APC/C function. We further provide evidence that curcumin preferably induces apoptosis in cells expressing phosphorylated Cdc27 usually found in highly proliferating cells.
  
  
  CONCLUSIONS
  We report that curcumin directly targets the SAC to induce apoptosis preferably in cells with high levels of phosphorylated Cdc27. Our studies provide a possible molecular mechanism why curcumin induces apoptosis preferentially in cancer cells and suggest that phosphorylation of Cdc27 could be used as a biomarker to predict the therapeutic response of cancer cells to curcumin.
authors.affiliation: Nemours/Alfred I, duPont Hospital for Children, Wilmington, DE 19803, USA.
authors.forename: Seung Joon
authors.initials: SJ
authors.lastname: Lee
authors.forename: Sigrid A
authors.initials: SA
authors.lastname: Langhans
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D064191:Apc3 Subunit, Anaphase-Promoting Complex-Cyclosome; D017209:Apoptosis / Q000187:drug effects*; D014408:Biomarkers, Tumor / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D018797:Cell Cycle Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D002528:Cerebellar Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D003474:Curcumin / Q000494:pharmacology*; D006801:Humans; D008527:Medulloblastoma / Q000188:drug therapy* / Q000378:metabolism; D010766:Phosphorylation / Q000502:physiology
chemical_list: D000970:Antineoplastic Agents; D064191:Apc3 Subunit, Anaphase-Promoting Complex-Cyclosome; D014408:Biomarkers, Tumor; C577366:CDC27 protein, human; D018797:Cell Cycle Proteins; D003474:Curcumin