Abstract
Plasminogen activator inhibitor-1 (PAI-1) is elevated in various cancers, where it has been shown to effect cell migration and invasion and angiogenesis. While, PAI-1 is a secreted protein, its intercellular levels are increased in cancer cells. Consequently, intracellular PAI-1 could contribute to cancer progression. While various small molecule inhibitors of PAI-1 are currently being investigated, none specifically target intracellular PAI-1. A class of inhibitors, termed aptamers, has been used effectively in several clinical applications. We previously generated RNA aptamers that target PAI-1 and demonstrated their ability to inhibit extracellular PAI-1. In the current study we explored the effect of these aptamers on intracellular PAI-1. We transiently transfected the PAI-1 specific aptamers into both MDA-MB-231 human breast cancer cells, and human umbilical vein endothelial cells (HUVECs) and studied their effects on cell migration, invasion and angiogenesis. Aptamer expressing MDA-MB-231 cells exhibited a decrease in cell migration and invasion. Additionally, intracellular PAI-1 and urokinase plasminogen activator (uPA) protein levels decreased, while the PAI-1/uPA complex increased. Moreover, a significant decrease in endothelial tube formation in HUVECs transfected with the aptamers was observed. In contrast, conditioned media from aptamer transfected MDA-MB-231 cells displayed a slight pro-angiogenic effect. Collectively, our study shows that expressing functional aptamers inside breast and endothelial cells is feasible and may exhibit therapeutic potential.
Highlights
The association between the plasminogen activator system and cancer progression is well documented [1,2,3,4]
The highly invasive and metastatic human MDA-MB-231 breast cancer cells, which express elevated levels of plasminogen activator inhibitor-1 (PAI-1) were used in these studies
Several studies have demonstrated that cancer cells produce a high level of endogenous PAI-1 [28,29,30,31]
Summary
The association between the plasminogen activator system and cancer progression is well documented [1,2,3,4]. High concentrations of PAI-1 correlate with a poor prognosis (i.e. the “PAI-1 paradox”) in various gynecological cancers including breast and ovarian [8,9]. This finding is paradoxical since PAI-1 inhibits uPA, which in turn should inhibit or slow cancer progression. PAI-1 has been shown to regulate tumor cell adhesion, migration, invasion, and angiogenesis [9,10,11]. This is partly because of its interaction with the basement membrane protein, vitronectin [12,13]. Despite a plethora of data supporting PAI-1’s role in cancer, there is still controversy concerning its exact influence on cancer progression, as it has been shown to exhibit both pro- and anti-tumor effects
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