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Adenosine diphosphate regulates MMP2 and MMP9 activity in malignant mesothelioma cells
Author(s) -
Muscella Antonella,
Cossa Luca Giulio,
Vetrugno Carla,
Antonaci Giovanna,
Marsigliante Santo
Publication year - 2018
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1111/nyas.13922
Subject(s) - mmp2 , mmp9 , matrix metalloproteinase , cancer research , chemistry , protein kinase b , mesothelioma , microbiology and biotechnology , downregulation and upregulation , phosphorylation , biology , biochemistry , medicine , pathology , gene
Although an association between cancer progression and matrix metalloproteinase (MMP) 2 and MPP9 expression has been known, the expression, nuclear localization, and physiologically controlled activation of these two MMPs have not been investigated in malignant mesothelioma cells. We examined the expression and intracellular localization of MMP2/9 in ZL55 malignant mesothelioma cells, as well as their regulation by ADP. Using real‐time PCR, we showed that activation of the P2Y1 receptor by ADP increased the expression of MMP2/9 mRNAs; MMP2/9 collected from conditioned media also showed an increase in activity; and ADP induced the nuclear localization of MMP2/9. The effects of ADP on transcription of the MMPs were due to activation of c‐Src, Akt, and NF‐κB, while ERK1/2 phosphorylation was needed for the increase in enzymatic activity and the regulation of nuclear import. We also showed that the nuclear localization of MMP2/9 induced by ADP causes the cleavage and inactivation of poly‐ADP‐ribose polymerase‐1. These findings may help to elucidate the mechanisms regulating MMP2/9 activation in ZL55 human epithelioid mesothelioma cells, and perhaps other cells. Therapeutic approaches that promote ADP accumulation in a tumor environment may constitute an effective means to induce anticancer activity.