Adenosine diphosphate regulates MMP2 and MMP9 activity in malignant mesothelioma cells

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.

CCL3–CCR5 axis contributes to progression of esophageal squamous cell carcinoma by promoting cell migration and invasion via Akt and ERK pathways

“…VEGF-A is involved in CCL3-dependent angiogenesis in osteosarcoma [ 23 ] and is also upregulated downstream of the CCL3–CCR5 axis in oral squamous cell carcinoma [ 27 ]. Activating the PI3K/Akt and MEK/ERK pathways induces the expressions of MMP-2, MMP-9, and VEGF-A in various malignancies including ESCC [ 62 – 65 ]. Our present results demonstrated that treatment with rhCCL3 upregulated the MMP2 mRNA expression in three ESCC cell lines universally, and the VEGFA mRNA expression in two ESCC cell lines.…”

Non-canonical Expression of Cardiac Troponin-T in Neuroendocrine Ethmoid Sinus Carcinoma Following Immune Checkpoint Blockade

“…Troponin subunits enhance the growth and migration of neoplastic cells (13). Adenosine diphosphate generated by CK produces energy for cellular functions, and stimulates the degradation of the extracellular matrix (14). We speculate that the accumulation of cardiac-specific proteins/enzymes may contribute to disease progression in a tumor environment.…”

Targeting SRC Family Kinases in Mesothelioma: Time to Upgrade

“…A recent study also implicated SFKs in regulating the expression of MMPs in MM [45], in which these ECM-degrading enzymes associate with more invasive and aggressive behavior [99][100][101]. In particular, this study showed that activation of the G protein-coupled purinergic receptor P2Y1 by Receptor tyrosine kinases (RTKs) are frequently overexpressed and hyperactivated in MM and cooperatively interact with SRC to signal to downstream effectors, such as the mitogen-activated protein kinase (MAPK) and AKT pathways, which promote cell proliferation and survival.…”

“…A recent study also implicated SFKs in regulating the expression of MMPs in MM [45], in which these ECM-degrading enzymes associate with more invasive and aggressive behavior [99][100][101]. In particular, this study showed that activation of the G protein-coupled purinergic receptor P2Y1 by adenosine diphosphate (ADP) triggered SFK-mediated upregulation of MMP2/9 in MM cells [45]. Interestingly, this work also revealed a possible non-canonical nuclear role of MMP2/9 in the ZL55 human epithelioid MM cell line; such nuclear function of MMPs was previously identified in other tumors [102] but remains to be further addressed in MM.…”

“…Many small molecules inhibiting SFKs and multiple other kinases (hereafter called “SFK inhibitors”, for simplicity) have been developed [ 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 ], some of which have also been used in MM preclinical [ 45 , 46 , 47 , 48 , 49 ] and clinical studies [ 50 , 51 ] ( Table 1 ).…”