Biperiden and mepazine inhibit MALT1 paracaspase activity and tumor growth in pancreatic cancer

Abstract

Background: MALT1 is a key mediator of NF-κB signaling playing a crucial role in pancreatic ductal adenocarcinoma (PDAC). In this study, the role of MALT1 paracaspase activity in PDAC and the effects of its deactivation by mepazine and biperiden were studied. Methods: MALT1 expression was analyzed by immunohistochemistry in 310 patients with PDAC. MALT1 paracaspase activity assays were performed with recombinant MALT1 protein and MALT1 protein from lysates of cancer cells upon biperiden and mepazine treatment. MALT1 protein and mRNA expressions were analyzed by Western blots and qRT-PCR. PDAC cell proliferation and apoptosis were assessed by MTT, Ki67 and cleaved caspase 3 assays in PDAC cell lines upon treatment. The effect of mepazine and biperiden on tumor size was evaluated by a xenograft mouse model. Neurologic scoring was performed to assess adverse effects. Results: MALT1 is expressed in 75% of PDACs but is absent in regular exocrine pancreatic tissue. MALT1 paracaspase activity was highly active in PDAC cells and was inhibited by both biperiden and mepazine, leading to reduction of nuclear c-Rel translocation and reduction of proliferation. MALT1 paracaspase activity is inhibited by mepazine and biperiden. Biperiden and mepazine reduced PDAC tumor progression showing only minor adverse effects in mice. Conclusion: MALT1 paracaspase activity is crucial for PDAC tumor progression and can be effectively inhibited by mepazine or biperiden leading to reduction of tumor growth.