Modulation of protein kinase C by curcumin; inhibition and activation switched by calcium ions

Background and purpose: Previous studies have identified the natural polyphenol curcumin as a protein kinase C (PKC) inhibitor. In contrast, we found significant stimulation of PKC activity following curcumin treatment. Thus, the mechanism of curcumin interaction with PKC was investigated. Experimental approach: We employed phosphorylation assays in the presence of soluble or membrane‐bound PKC substrates, followed by SDS–PAGE, autoradiography and phosphorylation intensity measurements. Key results: Curcumin inhibited PKC in the absence of membranes whereas stimulation was observed in the presence of membranes. Further analysis indicated that curcumin decreased PKC activity by competition with Ca 2+ stimulation of the kinase, resulting in inhibition of activity at lower Ca 2+ concentrations and stimulation at higher Ca 2+ concentrations. The role of the membrane is likely to be facilitation of Ca 2+ ‐binding to the kinase, thus relieving the curcumin inhibition observed at limited Ca 2+ concentrations. Curcumin was found to mildly stimulate the catalytic subunit of PKC, which does not require Ca 2+ for activation. In addition, studies on Ca 2+ ‐independent PKC isoforms as well as another curcumin target (the sarcoplasmic reticulum Ca 2+ ‐ATPase) confirmed a correlation between Ca 2+ concentration and the curcumin effects. Conclusions and Implications: Curcumin competes with Ca 2+ for the regulatory domain of PKC, resulting in a Ca 2+ ‐dependent dual effect on the kinase. We propose that curcumin interacts with the Ca 2+ ‐binding domains in target proteins. To our knowledge, this is the first study that defines an interaction domain for curcumin, and provides a rationale for the broad specificity of this polyphenol as a chemopreventive drug. British Journal of Pharmacology (2007) 150 , 200–208. doi: 10.1038/sj.bjp.0706970