Curcumin inhibits tyrosine kinase activity of p185neu and also depletes p185neu.
Curcumin, a natural compound present in turmeric, possessing both anti-inflammatory and antioxidant effects, has been studied vigorously as a chemopreventative in several cancer models. The erbB2/neu gene-encoded p185neu tyrosine kinase is a potent oncoprotein. Overexpression of p185neu in breast cancer is known to be a poor prognostic factor. We investigated the effect of curcumin on p185neu tyrosine kinase and on the growth of breast cancer cell lines. Curcumin dose-dependently inhibited p185neu autophosphorylation and transphosphorylation in vitro and depleted p185neu protein in vivo. It dissociated the binding of p185neu with GRP94 (glucose-regulated protein), a molecular chaperone, and enhanced the depletion of p185neu. The amount of p185neu protein on the cell membrane was drastically decreased after curcumin treatment. These data demonstrated a new mechanism of the anti-tyrosine kinase activity of curcumin. The growth of several breast cancer cell lines was inhibited; the IC50 ranged from 7 to 18 microM, which, however, did not correlate with the expression level of p185neu. Colony formation in the soft agar assay, a hallmark of the transformation phenotype, was preferentially suppressed in p185neu-overexpressing cell lines by 5 microM curcumin (% of control, basal level versus overexpression: 59.3 versus 16.7%; P < 0.001 by Student's t test). Because curcumin effectively inhibited p185neu tyrosine kinase activity by depleting p185neu and potently suppressed the growth of multiple breast cancer cell lines, its therapeutic potential in advanced breast cancer is worthy of further investigation.
Hong
R L
RL
Department of Oncology, National Taiwan University Hospital, Taipei.
Spohn
W H
WH
Hung
M C
MC
D000970:Antineoplastic Agents / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D003114:Colony-Forming Units Assay; D003474:Curcumin / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005455:Fluorescent Antibody Technique; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008565:Membrane Proteins / Q000378:metabolism; D008970:Molecular Weight; D010766:Phosphorylation; D011485:Protein Binding / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D003474:Curcumin; D004791:Enzyme Inhibitors; D018840:HSP70 Heat-Shock Proteins; D008565:Membrane Proteins; D011505:Protein-Tyrosine Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; C018551:glucose-regulated proteins