Growth factor/growth Factor Receptor Loops in Autocrine Growth Regulation of Human Prostate Cancer DU145 Cells

摘要

Autocrine growth factors produced by epithelial cells mediatethe development and proliferation of neoplastic humanprostate tissue. Various approaches have been usedto down-regulate neoplastic growth of prostate cancerusing natural flavonoids, soluble receptors, pseudo-ligands,monoclonal antibodies and tyrosine kinase inhibitors(tyrphostins). Selected growth factor/growth factorreceptor loops (mainly TGFá/EGFR and IGFs/IGFIR) havebeen proposed as regulators of prostate cancer cellgrowth. We have previously determined that blockadeof IGFIR or VEGF2R signaling pathways by tyrphostinAG1024 and SU1498 inhibits autocrine growth and viabilityof DU145 cells in vitro. Recently, we comparedthe activity of AG1024 and SU1498 with the inhibitingeffect of tyrphostin A23 (a selective inhibitor of EGFR).The results described in this paper confirm that DU145cells do not produce IGFI or EGF. In contrast, DU145cells produce a great amount of VEGF, much more thanTGFá (about 60-fold), and VEGF may be the real autocrinegrowth factor of the investigated cells. The resultsindicate that the growth of DU145 may be regulated byat least three autocrine loops: TGFá/EGFR, IGFII/IGFIRand VEGF/VEGFR2. Neither AG1024 nor SU1498 affectedthe production of TGFá substantially, which excludesthe possibility that IGFRs or VEGFR2 inhibitors arrestthe growth of these cells by inhibition of synthesis and/or secretion of TGFá. The obtained data indicate that alltree investigated tyrphostins (AG1024, SU1498 and A23)inhibit signal transmission by Akt (PKB), ERK(1/2), Srcand STAT in a similar manner. A comparison of the effectsof the investigated tyrphostins indicates that TGFá,IGFII and VEGF stimulate cell growth by affecting thesame signaling pathway. The hypothesis was confirmedby the effect of the investigated tyrphostins on activationof EGFR. All these inhibitors decreased phosphorylationof EGFR to the same extent, and after the same timeof incubation with cell culture. These results stronglysuggest that stimulation of EGFR kinase is the main stepin the initiation of mitogen signaling in DU145 cells, regardlessof the type of ligand (TGFá, IGFs or VEGF) andtheir specific receptors.