MT1-MMP expression level status dictates the in vitro action of lupeol on inflammatory biomarkers MMP-9 and COX-2 in medulloblastoma cells

Abstract

Local inflammation-induced extracellular matrix structural changes are a prerequisite to neoplastic invasion by pediatric intracranial tumors. Accordingly, increased expression of matrix metalloproteinases MMP-2 and MMP-9, two inflammation-induced matrix metalloproteinases (MMPs), may further aid the transformed cells either to infiltrate adjacent tissues or to enter the peripheral circulation. In the context of neuroinflammation, MMP-9 has been linked to processes such as blood-brain barrier opening and invasion of neural tissue by blood-derived immune cells. Given its reported anti-inflammatory and anticancer properties, we investigated the in vitro pharmacological effects of lupeol, a diet-derived triterpenoid, on MMP-9 and cyclooxygenase (COX)-2 expressions in a pediatric medulloblastoma DAOY cell line model. Lupeol was unable to inhibit the increased MMP-9 and COX-2 expression in phorbol 12-myristate 13-acetate (PMA)-treated cells, but was rather found to synergize with PMA to induce both biomarkers' expression. A contribution of the membrane type-1 (MT1)-MMP was also revealed, since lupeol/PMA treatments triggered proMMP-2 activation, and that MT1-MMP gene silencing reversed the combined effects of lupeol/PMA on both MMP-9 and COX-2. The mRNA stabilizing factor HuR was also found increased in the combined lupeol/PMA treatment, suggesting stabilization processes of the MMP-9 and COX-2 transcripts. We postulate that lupeol's anti-inflammatory properties may exert better pharmacological action within low MT1-MMP expressing tumors. Furthermore, these evidences add up to the new pleiotropic molecular mechanisms of action of MT1-MMP, and prompt for evaluating the future in vitro pharmacological properties of lupeol under pro-inflammatory experimental set-up.