All-trans Retinoic Acid (ATRA), a Potential Inhibitor of Matrix Metalloproteinase-2 (MMP-2) and Tumour Invasion in Melanomas

Increased expression and activity of matrix metalloproteinase-2 (MMP-2) has been correlated with an
increase in invasive potential and a worse prognosis in many cancers including melanomas. The antitumorigenic
potential of all-trans retinoic acid (ATRA) in melanomas was studied using the highly
metastatic murine melanoma cell line B16F10 as a model. Treatment of B16F10 cells with 20 μM/ml
ATRA for 24 hrs caused a significant downregulation of MMP-2 expression and activity. Inhibition of
MMP-2 activity appeared to be mediated via a significant decrease in expression of membrane type-1
matrix metalloproteinase (MT1-MMP), a crucial component of the MMP-2 activation complex, and
extracellular matrix metalloproteinase inducer (EMMPRIN) and a significant increase in expression of
tissue inhibitor of metalloproteinases-2 (TIMP-2). Downregulation of MMP-2 expression and activity
would appreciably lower the invasive potential of melanoma cells. Inhibition of phosphorylation of focal
adhesion kinase (FAK) upon ATRA treatment could inhibit intracellular signalling cascades and also
downregulate MMP-2 levels and cell migration. The effectiveness of ATRA in inhibiting the migratory
capabilities of B16F10 cells was confirmed by wound healing assay. Our findings thus elucidate
important aspects about the molecular mechanisms of the effect of ATRA treatment on MMP-2 in
melanomas and also indicate the anti-tumorigenic potential of ATRA which could have therapeutic
value in clinical management of invasive melanomas.