Procyanidins Negatively Affect the Activity of the Phosphatases of Regenerating Liver

Abstract

Natural polyphenols like oligomeric catechins (procyanidins) derived from green tea and herbal medicines are interesting compounds for pharmaceutical research due to their ability to protect against carcinogenesis in animal models. It is nevertheless still unclear how intracellular pathways are modulated by polyphenols. Monomeric polyphenols were shown to affect the activity of some protein phosphatases (PPs). The three phosphatases of regenerating liver (PRLs) are close relatives and promising therapeutic targets in cancer. In the present study we show that several procyanidins inhibit the activity of all three members of the PRL family in the low micromolar range, whereas monomeric epicatechins show weak inhibitory activity. Increasing the number of catechin units in procyanidins to more than three does not further enhance the potency. Remarkably, the tested procyanidins showed selectivity in vitro when compared to other PPs, and over 10-fold selectivity toward PRL-1 over PRL-2 and PRL-3. As PRL overexpression induces cell migration compared to control cells, the effect of procyanidins on this phenotype was studied. Treatment with procyanidin C2 led to a decrease in cell migration of PRL-1- and PRL-3-overexpressing cells, suggesting the compound-dependent inhibition of PRL-promoted cell migration. Treatment with procyanidin B3 led to selective suppression of PRL-1 overexpressing cells, thereby corroborating the selectivity toward PRL-1- over PRL-3 in vitro. Together, our results show that procyanidins negatively affect PRL activity, suggesting that PRLs could be targets in the polypharmacology of natural polyphenols. Furthermore, they are interesting candidates for the development of PRL-1 inhibitors due to their low cellular toxicity and the selectivity within the PRL family.

Effect of Pharmacological Inhibition of the Catalytic Activity of Phosphatases of Regenerating Liver in Early T Cell Receptor Signaling Dynamics and IL-2 Production

“…As expected, the MEK inhibitor U0126 indicated the dependence of IL-2 production in MAPK signaling. Consistent with our previous data obtained in peripheral blood T cells [12] and in the treatment with JMS-053, thienopyridone (TP), which also inhibits the catalytic activity of all PRLs [24], produced a more drastic reduction of the IL-2 production than procyanidin B3 (PB3), a more selective inhibitor of PRL-1 [25] ( Figure 3C). TP, JMS-038 and JMS-053 compounds are structurally related [23] and consequently the effect of TP was also higher than the effect of the control compound JMS-038.…”

Phosphatase of Regenerating Liver-1 (PRL-1) Regulates Actin Dynamics During Immunological Synapse Assembly and T Cell Effector Function

“…We further studied whether the catalytic activity of PRL-1 regulated F-actin dynamics during T cell activation by using procyanidin B3 (PB3), a selective inhibitor of PRL-1 catalytic activity ( 23 ). Peripheral blood CD4 T cells were enabled to form IS-like structures with micro-spheres coated with anti-CD3ε and anti-CD28 antibodies, and F-actin polymerization at the IS was evaluated by phalloidin staining.…”

Expression of phosphatase of regenerating liver (PRL)-3, is independently associated with biochemical failure, clinical failure and death in prostate cancer

“…There are currently no ongoing clinical studies targeting PRL-3. However, over the last decade multiple novel PRL-3 inhibitors have been developed[ 48 – 53 ] and several natural occurring compounds are found to have PRL-3-inhibitory properties[ 54 – 58 ], both with clear in vitro effects on various types of cancer cells. In vitro studies have also investigated effects of PRL-3 inhibition on PC cells.…”