Sawai Hirozumi, Liu Joey, Reber Howard A, Hines Oscar J, Eibl Guido
Hirshberg Laboratory for Pancreatic Cancer Research, Department of Surgery, David Geffen School of Medicine, University of California at Los Angeles, 675 Charles E. Young Drive South, MRL 2535, Los Angeles, CA 90095, USA.
Mol Cancer Res. 2006 Mar;4(3):159-67. doi: 10.1158/1541-7786.MCR-05-0257.
Cancer cell invasion and metastasis require the concerted action of several proteases that degrade extracellular matrix proteins and basement membranes. Recent reports suggest the plasminogen activator system plays a critical role in pancreatic cancer biology. In the present study, we determined the contribution of the plasminogen activator system to pancreatic cancer cell invasion in vitro. Moreover, the effect of peroxisome proliferator-activated receptor (PPAR)-gamma ligands, which are currently in clinical use as antidiabetic drugs and interestingly seem to display antitumor activities, on pancreatic cancer cell invasion and the plasminogen activator system was assessed. Expression of components of the plasminogen activator system [i.e., urokinase-type plasminogen activator (uPA), plasminogen activator inhibitor-1, and uPA receptor] was detected in six human pancreatic cancer cell lines. Inhibition of urokinase activity by specific synthetic compounds reduced baseline pancreatic cancer cell invasion. The PPAR-gamma ligands 15-deoxy-Delta12,14-prostaglandin J2 and ciglitazone also attenuated pancreatic cancer cell invasion. This effect was abrogated by dominant-negative PPAR-gamma receptors and pharmacologic PPAR-gamma inhibitors. Moreover, activation of PPAR-gamma by ligands increased plasminogen activator inhibitor-1 and decreased uPA levels in pancreatic cancer cells, and this was accompanied by a reduction in total urokinase activity. The present study shows that the plasminogen activator system plays an integral role in pancreatic cancer cell invasion in vitro. Activation of the nuclear receptor PPAR-gamma by ligands reduced pancreatic cancer cell invasion, which was largely mediated by modulation of the plasminogen activator system. These findings further underscore the potential role of PPAR-gamma ligands as therapeutic agents in pancreatic cancer.
癌细胞的侵袭和转移需要多种蛋白酶协同作用，这些蛋白酶可降解细胞外基质蛋白和基底膜。最近的报道表明，纤溶酶原激活物系统在胰腺癌生物学中起着关键作用。在本研究中，我们确定了纤溶酶原激活物系统在体外对胰腺癌细胞侵袭的作用。此外，还评估了目前作为抗糖尿病药物使用且有趣的是似乎具有抗肿瘤活性的过氧化物酶体增殖物激活受体（PPAR）-γ配体对胰腺癌细胞侵袭和纤溶酶原激活物系统的影响。在六种人胰腺癌细胞系中检测到了纤溶酶原激活物系统各组分[即尿激酶型纤溶酶原激活物（uPA）、纤溶酶原激活物抑制剂-1和uPA受体]的表达。特定合成化合物对尿激酶活性的抑制降低了胰腺癌细胞的基线侵袭能力。PPAR-γ配体15-脱氧-Δ12,14-前列腺素J2和吡格列酮也减弱了胰腺癌细胞的侵袭。显性负性PPAR-γ受体和PPAR-γ药理学抑制剂消除了这种作用。此外，配体激活PPAR-γ可增加胰腺癌细胞中纤溶酶原激活物抑制剂-1的水平并降低uPA水平，同时总尿激酶活性也随之降低。本研究表明，纤溶酶原激活物系统在体外胰腺癌细胞侵袭中起着不可或缺的作用。配体激活核受体PPAR-γ可降低胰腺癌细胞的侵袭，这在很大程度上是通过调节纤溶酶原激活物系统介导的。这些发现进一步强调了PPAR-γ配体作为胰腺癌治疗药物的潜在作用。
