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

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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.

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Abbreviations

COX:

Cyclooxygenase

IL:

Interleukin

MMP:

Matrix metalloproteinase

MT1-MMP:

Membrane type-1 MMP

NF-κB:

Nuclear factor kappa B

PMA:

Phorbol 12-myristate 13-acetate

PGE:

Prostaglandin E

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Acknowledgments

BA holds a Canada Research Chair in Molecular and Metabolic Oncology from the Canadian Institutes of Health Research (CIHR). RB holds an Institutional UQAM Research Chair in Cancer Prevention and Treatment. This study was funded by grants from the Natural Sciences and Engineering Research Council of Canada (NSERC) to RB.

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Authors and Affiliations

  1. Laboratoire d’Oncologie Moléculaire, Centre de Recherche BioMED, Université du Québec à Montréal, Quebec, Canada

    Borhane Annabi & Eric Vaillancourt-Jean

  2. Laboratoire de Médecine Moléculaire, Centre de Recherche BioMED, Université du Québec à Montréal, C.P. 8888, Succ. Centre-ville, Montreal, QC, H3C 3P8, Canada

    Richard Béliveau

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  1. Borhane Annabi
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  2. Eric Vaillancourt-Jean
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  3. Richard Béliveau
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Correspondence to Borhane Annabi.

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B. Annabi and E. Vaillancourt-Jean contributed equally to this work.

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Annabi, B., Vaillancourt-Jean, E. & Béliveau, R. MT1-MMP expression level status dictates the in vitro action of lupeol on inflammatory biomarkers MMP-9 and COX-2 in medulloblastoma cells. Inflammopharmacol 21, 91–99 (2013). https://doi.org/10.1007/s10787-012-0142-8

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  • DOI: https://doi.org/10.1007/s10787-012-0142-8

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