Role of plasminogen activator inhibitor-1 in urokinase's paradoxical in vivo tumor suppressing or promoting effects.
نویسندگان
چکیده
Tumor proteases and inhibitors have been associated with paradoxical effects on tumor progression in preclinical and clinical settings. We previously reported that urokinase (uPA) overexpression delays tumor progression in mammary cancer. This study aimed to determine the role of plasminogen activator inhibitor-1 (PAI-1) on uPA's paradoxical in vivo effects. Using syngeneic murine models, we found that stable uPA overexpression promoted in vivo growth of colon tumors (MC-38) naturally expressing high PAI-1, whereas growth inhibition was observed in renal tumors (RENCA) expressing lower PAI-1 levels. In murine mammary carcinoma (4T1), uPA overexpression shifted the uPA/PAI-1 balance in favor of the protease, resulting in significantly reduced tumor growth and metastases in vivo. Conversely, increased tumor progression was observed in stable PAI-1 overexpressing 4T1 tumors as compared with uPA-overexpressing and control tumors. These effects were associated with downregulation of metastases promoting genes in uPA-overexpressing tumors, such as metalloproteinases, CXCL-1, c-Fos, integrin α-5, VEGF-A, PDGF-α, and IL-1β. In PAI-1-overexpressing tumors, many of the above genes were upregulated. PAI-1 overexpressing tumors had increased total and new tumor microvessels, and increased tumor cell proliferation, whereas the opposite effects were found in uPA-overexpressing tumors. Finally, PAI-1 downregulation led to significant inhibition of 4T1 tumor growth and metastases in vivo. In conclusion, uPA's dual effects on tumor progression occur in the context of its interactions with endogenous PAI-1 expression. Our studies uncover novel mechanisms of in vivo tumor control by modulation of the balance between tumor proteases and inhibitors, which may be exploited therapeutically.
منابع مشابه
Optimizing refolding condition for recombinant tissue plasminogen activator
Low molecular size additives such as L-arginine and the redox compounds have been used both in the culturemedium and in vitro refolding to increase recombinant proteins production. Additives increase proteinrefolding and yield of active proteins by suppressing aggregate formation or enhancing refolding process.In this work, a comparative study was performed on refolding of rec...
متن کاملPlasminogen Activator Inhibitor-1 in Cancer: Rationale and Insight for Future Therapeutic Testing.
Despite its function as an inhibitor of urokinase and tissue-type plasminogen activator (PA), PA inhibitor-1 (PAI-1) has a paradoxical protumorigenic role in cancer, promoting angiogenesis and tumor cell survival. In this review, we summarize preclinical evidence in support of the protumorigenic function of PAI-1 that has led to the testing of small-molecule PAI-1 inhibitors, initially develope...
متن کاملThe Effects of Regular Aerobic Exercise on the serum levels of Plasminogen Activator Inhibitor-1 and Adiponectin in Obese Girls
Background: The modification of the adipokine levels can be important for the long-term prevention of systemic inflammation related to obesity in children. Objective: The current study aimed to investigate the effects of regular aerobic exercise on the serum levels of plasminogen Activator inhibitor-1(PAI-1) and Adiponectin in obese girls. Methods: This semi experimental research, 14 obese gi...
متن کاملSerum Level of Plasminogen Activator Inhibitor Type-1 in Addicted Patients with Coronary Artery Disease
Background: Plasminogen activator inhibitor-1 (PAI-1) is a glycoprotein with inhibitory effects on the formation of plasmin from plasminogen by plasminogen activator. Thus, it prevents clot lysis in vessel walls. Several evidences prove the relationship between coronary artery disease and response to fibrinolytic therapy in patients with myocardial infarction with PAI-1 level. Opium addiction i...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
عنوان ژورنال:
- Molecular cancer research : MCR
دوره 10 10 شماره
صفحات -
تاریخ انتشار 2012