Department of Biological and Environmental Sciences and Technologies (Di.S.Te.B.A.), University of Salento, Lecce, Italy.
Ann N Y Acad Sci. 2018 Nov;1431(1):72-84. doi: 10.1111/nyas.13922. Epub 2018 Jul 8.
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.
虽然已经知道癌症进展与基质金属蛋白酶 (MMP) 2 和 MMP9 表达之间存在关联，但恶性间皮瘤细胞中这两种 MMP 的表达、核定位和生理控制激活尚未得到研究。我们研究了 ZL55 恶性间皮瘤细胞中 MMP2/9 的表达和细胞内定位，以及它们被 ADP 的调节。通过实时 PCR，我们表明 ADP 通过激活 P2Y1 受体增加 MMP2/9 mRNA 的表达；从条件培养基中收集的 MMP2/9 也显示活性增加；ADP 诱导 MMP2/9 的核定位。ADP 对 MMP 转录的影响归因于 c-Src、Akt 和 NF-κB 的激活，而 ERK1/2 磷酸化对于酶活性的增加和核输入的调节是必需的。我们还表明，ADP 诱导的 MMP2/9 核定位导致多聚 ADP-核糖聚合酶-1 的裂解和失活。这些发现可能有助于阐明调节 ZL55 人上皮样间皮瘤细胞中 MMP2/9 激活的机制，也许还有其他细胞。促进 ADP 在肿瘤环境中积累的治疗方法可能构成诱导抗癌活性的有效手段。
