Abstract
Small‐cell lung carcinoma releases progalanin. The released progalanin is activated via a nonclassical processing pathway, being processed into an active form of galanin (1–20) by plasmin in extracellular components. Plasmin is produced from plasminogen activators. To clarify the regulation of progalanin via plasminogen activation by urokinase and tissue‐plasminogen activator (t‐PA), we investigated the regulation mechanism for urokinase and t‐PA expression and their effect on galanin activation. Additionally, we studied the effect of activated galanin on angiogenesis. To determine the effect of cell density, we measured the expression levels of urokinase and t‐PA using real‐time PCR and plasminogen/gelatin zymography in a cell culture. The urokinase expression increased under both high cell density and presence of cell membrane fractions. However, urokinase increments induced by conditioned medium were low. These results indicate that expression of plasminogen activators is regulated by cell membrane factors. We used tumor‐bearing mice to clarify the expression of plasminogen activators and galanin activation. Real‐time PCR showed that urokinase was substantially higher in the central parts of tumors compared to the periphery, and this was confirmed by plasminogen/gelatin zymography. To evaluate the biological effect of plasminogen activators on tumor growth, we used tranexamic acid as a plasminogen inhibitor. Tranexamic acid decreased galanin (1–20) and the hemoglobin content of tumors and suppressed tumor growth. Additionally, galanin had no effect on the hemoglobin content of tumors derived from cells lacking GALR2. These results demonstrate the regulation of urokinase expression in tumors through progalanin activation in extracellular compartments, and confirm that galanin plays a role in angiogenesis.
Highlights
We assessed the effects of cell adhesion via coculturing with cell membranes prepared from SBC-3A cells and evaluated tumor factors using SBC-3A cells in culture-conditioned media
The effect of plasminogen activators on galanin activation and tumor growth We evaluated tumor growth by measuring cell diameter after implanting small-cell lung carcinoma cells mixed in Matrigel (Fig. 3A)
The plasminogen system is a well-known angiogenesis mechanism involved in tumor growth [35,36]. u-PA in particular was found to be widely expressed in several cancer cells and to play a role in tumor progression, invasion, and metastasis [8]
Summary
Urokinase increments induced by conditioned medium were low These results indicate that expression of plasminogen activators is regulated by cell membrane factors. Galanin had no effect on the hemoglobin content of tumors derived from cells lacking GALR2. These results demonstrate the regulation of urokinase expression in tumors through progalanin activation in extracellular compartments, and confirm that galanin plays a role in angiogenesis. There are many reports on the effects of plasmin on Abbreviations Hb, hemoglobin; HRP, horseradish peroxidase; MMP, matrix metalloproteinase; RIA, radioimmunoassay; SCLC, small-cell lung carcinoma; t-PA, tissue-plasminogen activator; u-PA, urokinase. Urokinase regulates activation of galanin in tumor tumor growth, invasion, and metastasis, its effect on angiogenesis and cell migration [5,6]. Some cancer cells produce u-PA and there is a positive correlation between the amount of u-PA expression and malignancy [8,9]
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