| Abstract: | Bothhyaluronidase and transforming growth factor (TGF)- 1 play asignificant role in the development of prostate cancer. In this study,the regulation of tumor necrosis factor (TNF)-mediated cell death byhyaluronidase and TGF-1 was investigated. Preexposure of L929fibroblasts, prostate LNCaP cells, and epithelial Mv 1 Lu cells tohyaluronidase for a minimum of 12 h resulted in significant enhancementof cell death by TNF. Phosphorylation of p42 and p44 mitogen-activatedprotein (MAP) kinases was found by stimulation of L929 cells withhyaluronidase for 30 min, indicating that the Raf/MAPkinase-extracellular signal-regulating protein kinase (MEK)/MAP kinase pathway was activated. However, blocking the activation of upstream MAP kinase kinase (MEK 1 and 2 kinase) byPD-98059 failed to inhibit the hyaluronidase-enhanced TNF killing ofcells, suggesting that hyaluronidase-mediated degradation of extracellular matrix and membrane components may elicit multiple signaling pathways. As a potent stimulator of extracellular matrix protein synthesis, TGF-1 blocked the hyaluronidase-enhanced death ofL929 and LNCaP cells mediated by TNF. TGF-1 activatedprotein-tyrosine kinases in L929 cells, in which the tyrosine kinaseinhibitors lavendustin A and tyrphostin blocked the activation as wellas the TGF-1 inhibition of hyaluronidase effects. Functionalantagonism was also observed between hyaluronidase and TGF-1 in cellgrowth regulation. For example, TGF-1-mediated suppression ofepithelial Mv 1 Lu cell growth was abolished by hyaluronidase. Overall,it is demonstrated in this study that hyaluronidase reciprocally antagonized TGF-1 in the modulation of cell proliferation and TNF-mediated death. |
