A new curcumin derivative, HBC, interferes with the cell cycle progression of colon cancer cells via antagonization of the Ca2+/calmodulin function.
HBC (4-[3,5-Bis-[2-(4-hydroxy-3-methoxy-phenyl)-ethyl]-4,5-dihydro-pyrazol-1-yl]-benzoic acid) is a recently developed curcumin derivative which exhibits potent inhibitory activities against the proliferation of several tumor cell lines. In the present study, we identified Ca2+/calmodulin (Ca2+/CaM) as a direct target protein of HBC using phage display biopanning. Ca2+/CaM-expressing phages specifically bound to the immobilized HBC, and the binding was Ca2+ dependent. Moreover, flexible docking modeling demonstrated that HBC is compatible with the binding cavity for a known inhibitor, W7, in the C-terminal hydrophobic pocket of Ca2+/CaM. In biological systems, HBC induced prolonged phosphorylation of ERK1/2 and activated p21(WAF1) expression, resulting in the induction of G0/G1 cell cycle arrest in HCT15 colon cancer cells. These results suggest that HBC inhibits the cell cycle progression of colon cancer cells via antagonizing of Ca2+/CaM functions.
Chemical Genomics National Research Laboratory, Department of Bioscience and Biotechnology, Institute of Bioscience, Sejong University, Seoul 143-747, Korea.
Joong Sup
JS
Shim
Jiyong
J
Lee
Hyun-Ju
HJ
Park
So-Jung
SJ
Park
Ho Jeong
HJ
Kwon
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites / Q000502:physiology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002417:Cattle; D002453:Cell Cycle / Q000187:drug effects* / Q000502:physiology; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000201:enzymology*; D003474:Curcumin / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D008969:Molecular Sequence Data
D017871:Calcium-Calmodulin-Dependent Protein Kinases; D003474:Curcumin