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 Ca²⁺ stimulation of the kinase, resulting in inhibition of activity at lower Ca²⁺ concentrations and stimulation at higher Ca²⁺ concentrations. The role of the membrane is likely to be facilitation of Ca²⁺‐binding to the kinase, thus relieving the curcumin inhibition observed at limited Ca²⁺ concentrations. Curcumin was found to mildly stimulate the catalytic subunit of PKC, which does not require Ca²⁺ for activation. In addition, studies on Ca²⁺‐independent PKC isoforms as well as another curcumin target (the sarcoplasmic reticulum Ca²⁺‐ATPase) confirmed a correlation between Ca²⁺ concentration and the curcumin effects.

Conclusions and Implications:

Curcumin competes with Ca²⁺ for the regulatory domain of PKC, resulting in a Ca²⁺‐dependent dual effect on the kinase. We propose that curcumin interacts with the Ca²⁺‐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.

DOI: 10.1038/sj.bjp.0706970

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