Zinc Protoporphyrin Suppresses β-Catenin Protein Expression in Human Cancer Cells: The Potential Involvement of Lysosome-Mediated Degradation

Zinc protoporphyrin (ZnPP) has been found to have anticancer activity both in vitro and in vivo. We have recently demonstrated that ZnPP diminishes beta-catenin protein expression in cancer cells. The present study examined the cellular mechanisms that mediate ZnPP's suppression of beta-catenin expression. We demonstrate that ZnPP induces a rapid degradation of the beta-catenin protein in cancer cells, which is accompanied by a significant inhibition of proteasome activity, suggesting that proteasome degradation does not directly account for the suppression. The possibility that ZnPP induces beta-catenin exportation was rejected by the observation that there was no detectable beta-catenin protein in the conditioned medium after ZnPP treatment of cancer cells. Further experimentation demonstrated that ZnPP induces lysosome membrane permeabilization, which was reversed by pretreatment with a protein transportation inhibitor cocktail containing Brefeldin A (BFA) and Monensin. More significantly, pretreatment of cancer cells with BFA and Monensin attenuated the ZnPP-induced suppression of beta-catenin expression in a concentration-and time-dependent manner, indicating that the lysosome protein degradation pathway is likely involved in the ZnPP-induced suppression of beta-catenin expression. Whether there is cross-talk between the ubiquitin-proteasome system and the lysosome pathway that may account for ZnPP-induced beta-catenin protein degradation is currently unknown. These findings provide a novel mechanism of ZnPP's anticancer action and reveal a potential new strategy for targeting the beta-catenin Wnt signaling pathway for cancer therapy.