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.

A Role for the Cavin-3/Matrix Metalloproteinase-9 Signaling Axis in the Regulation of PMA-Activated Human HT1080 Fibrosarcoma Cell Neoplastic Phenotype

“…20 As is the case for cavin-3, MMP-9 can also be activated by TNF-α, PMA, and EGF. 36,44,50,51 Here, we show that PMA effectively induces MMP-9 transcription and secretion in HT-1080 fibrosarcoma cells, but that this induction in MMP-9 is actually the result of a change in the balance between PMAinduced MMP-9 and cavin-3 signaling (summarized in Fig. 6).…”

“…In this study, we used a human fibrosarcoma cell line that responded to PMA in part through increased secretion of MMP-9, 33 the secretion of which is classicaly correlated with pro-inflammatory, 35 , 36 pro-angiogenic and metastatic processes. 37 Our study demonstrates that, although both MMP-9 expression and cell migration can effectively be triggered in vitro upon a defined PMA treatment, the overall effect that is actually measured is, in fact, a diminished cell migration index, in part consequent to the increased expression of the tumor suppressor cavin-3.…”

A Transcriptional Regulatory Role for the Membrane Type-1 Matrix Metalloproteinase in Carcinogen-Induced Inflammasome Gene Expression

“…More recently, the MT1-MMP expression level status was found to dictate the in vitro action of lupeol on PMA-induced inflammatory biomarkers MMP-9 and COX-2 in a pediatric brain tumor cell model. 60…”