Natural polyphenols that selectively inhibit CaM kinase phosphatase (CaMKP/PPM1F/POPX2) suppress cancer cell migration.

CaM kinase phosphatase (CaMKP/PPM1F/POPX2) is widely expressed in various tissues and organs, and increasing evidence suggests its involvement in the pathogenesis of several diseases, including cancers. In this study, we identified a class of natural polyphenolic compounds with a pyrogallol structure as potent inhibitors of CaMKP. These compounds selectively inhibited CaMKP via protein carbonylation, while showing negligible effects on PPM1A or λ-phosphatase. Among the polyphenols tested, dihydromyricetin, myricetin, and delphinidin potently inhibited CaMKP, with dihydromyricetin being more potent than ethyl gallate, which was recently reported as a selective CaMKP inhibitor. The carbonylation of CaMKP by these polyphenols was restored by a free radical scavenger, cysteamine, suggesting that this inhibitory process involves free radical-mediated oxidative reactions. Taxifolin, an analogue of dihydromyricetin lacking one phenolic hydroxy group, failed to induce the carbonylation or inhibition of CaMKP, indicating the essential role of the pyrogallol moiety. Consistent with these findings, dihydromyricetin and myricetin significantly inhibited the migration of CaMKP-overexpressing MDA-MB-231 breast cancer cells, whereas their structural analogues taxifolin and quercetin showed no or only weak inhibitory effects. In addition, some other pyrogallol-containing polyphenols tested (delphinidin, scutellarein, baicalein) also exhibited significant inhibitory effects. In contrast, these polyphenols showed little to no inhibitory effects on the migration of T47D cells, in which CaMKP expression level is relatively low. Notably, the inhibition of migration by these pyrogallol-containing polyphenols, except quercetin, was not accompanied by significant cytotoxicity. Thus, these polyphenols are promising candidates for suppressing CaMKP-dependent cancer metastasis with minimal side effects.