Adenosine diphosphate regulates MMP2 and MMP9 activity in malignant mesothelioma cells

Our plain-English summary of Adenosine diphosphate regulates MMP2 and MMP9 activity in malignant mesothelioma cells, by A. Muscella, L.G. Cossa, C. Vetrugno, et al (Annals of the New York Academy of Sciences, 2018).

The study

• Authors: A. Muscella, L.G. Cossa, C. Vetrugno, G. Antonaci, S. Marsigliante
• Journal: Annals of the New York Academy of Sciences
• Published: 2018;1431(1):72-84
• Cited by: 9 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

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.

© 2018 New York Academy of Sciences.

In plain English

This was a laboratory study of a single human mesothelioma cell line called ZL55. The authors describe it as epithelioid and as obtained from an asbestos-exposed patient. The experiments described used only cultured cells, and the cells were not exposed to asbestos. The authors treated the cells with ADP, a natural signaling molecule, and measured two enzymes, MMP2 and MMP9. ADP raised the cells' production of both enzymes and their activity, depending on dose and time. In untreated cells only MMP9 was found in the cell nucleus. After ADP treatment, both enzymes increased in the nucleus. Blocking the signaling proteins NF-kappaB, Akt or c-Src reduced these effects. Blocking ERK1/2 reduced enzyme activity and movement into the nucleus, while total enzyme levels appeared unchanged. ADP also led to the cutting of PARP-1, a DNA-repair protein, and an MMP2/9 inhibitor reduced this. The authors concluded that ADP could enhance PARP-1 cleavage by MMP2/9 through these signaling pathways. They suggested that treatments promoting ADP build-up in tumors may be a way to induce anticancer activity.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: laboratory cell-culture experiment (in vitro) on one mesothelioma cell line
• Who was studied: ZL55 human epithelioid malignant mesothelioma cells grown in culture. The authors state the line was obtained from an asbestos-exposed patient. Experiments were repeated five or six times on separate cultures. The experiments described used cultured cells only, and no patients were studied. The statistical methods section mentions animals, but no animal experiments are described.
• Exposure: Cells were treated with ADP (adenosine diphosphate) at various concentrations and times. 2-MeS-ADP gave comparable results. Inhibitors of Akt/PI3K, c-Src, ERK1/2 and MMP2/9, and siRNA against p65/NF-kappaB, were used to test the signaling pathways. The cells were not exposed to asbestos fibers in these experiments.
• Main results:
  • In ZL55 cells, ADP increased MMP2 and MMP9 mRNA levels in a time- and dose-dependent manner. It also increased their protein levels and gelatinase activity.
  • In untreated ZL55 cells only MMP9 was found in the nucleus. ADP treatment increased both MMP2 and MMP9 in the nucleus.
  • By immunofluorescence microscopy, MMP2 and MMP9 were spread through the cytosol. After 18 hours of ADP treatment, the staining was concentrated in the nuclei.
  • Silencing p65/NF-kappaB with siRNA blocked ADP's effects on MMP2/9 mRNA, protein and nuclear activity. A non-specific control siRNA had no effect.
  • Inhibiting Akt (with LY294002) or c-Src (with PP1) blocked ADP-induced MMP2/9 expression and activity.
  • The ERK1/2 pathway inhibitor PD98059 reduced the activity of secreted and nuclear MMP2/9. Total MMP2/9 protein levels appeared unchanged.
  • After 3 hours of ADP treatment, full-length PARP-1 (116 kDa) was cut into 89 and 43 kDa fragments over time. An MMP2/9 inhibitor significantly decreased this ADP-induced PARP-1 degradation.
• The authors' conclusion: The authors concluded that ADP could enhance PARP-1 cleavage by MMP2/9 through the PI3K/Akt/NF-kappaB and ERK1/2 signaling pathways. They suggested that therapeutic approaches promoting ADP accumulation in a tumor environment may be an effective means to induce anticancer activity.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Malignant Mesothelioma, Epithelioid, Mesothelioma.

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• Slug enhances invasion ability of pancreatic cancer cells through upregulation of matrix metalloproteinase-9 and actin cytoskeleton remodeling — K. Zhang, D. Chen, et al. (2011)

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