Since a high basal level of phosphorylated c Met is also observed in PC 3 cells, it was anticipated that an HGFc Met autocrine loop that induces newsletter subscribe constitutive c Met activation exist in this cell line. However, the molecular weight of the secreted HGF by PC 3 cells was inconsistent with the recombinant HGF protein. Furthermore, c Met associated func tions were not activated by CM from PC 3 cells, suggesting that what was secreted by these cells was not functional HGF. This conclusion was subsequently Inhibitors,Modulators,Libraries supported by evidence indicating that PC 3 cells did not respond to the anti HGF neutralizing antibody. a finding that supports the conclu sion that the constitutive c Met activity in PC 3 cells is autocrine independent. Two questions arise from the results of the current study.

Firstly, what is the HGF produced by PC 3 cells and what is its functionMature HGFSF is composed of an chain and a B chain that Inhibitors,Modulators,Libraries are linked to form a heterodimer. Since the primers Inhibitors,Modulators,Libraries are designed to probe the subunit of HGF mRNA and a single band can be detected under non reducing conditions, the secreted protein might be an isoform Inhibitors,Modulators,Libraries of HGF. Secondly, if an autocrine loop is not involved, then what accounts for the constitutive c Met activationTo date MET gene abnormalities such as activating mutations or amplifications have not been reported in PC 3 cells nor prostate cancer in general, suggesting alterations at the genetic level may not be involved. Since c Met pro tein overexpression due to mRNA upregulation occurs predominantly in human cancers, the basal level of phosphorylated c Met in PC 3 cells may simply be a re sult of increased MET transcripts via unknown mechan isms.

In addition, the cross talk between c Met and other signaling Inhibitors,Modulators,Libraries molecules post transcriptionally could be a possibility given that c Met is able to be transactivated by several other transmembrane proteins. In the PC 3 cell line, basal c Met phosphorylation remained unaffected by exposure to either gefitinib or dasatinib, suggesting that c Met is not activated by epidermal growth factor receptor or c Src, two kinases shown to be involved in c Met transactiva tion in some studies. However other signaling molecules such as Ron, another Met receptor family member which is also overexpressed in PC 3 cells, might transactivate c Met. Finally, an HGF mediated intracellular autocrine mechanism, although rare, could be another possibility.

Despite the unresponsiveness of PC 3 cells to anti HGF antibody, the Met kinase inhibitor BMS 777607 did significantly inhibit PC 3 cell proliferation, clo nogenicity, migration and invasion as well as c Met signaling pathways. Coupled with our previous findings, these results suggest that in the PC 3 tumor model, c Met signaling plays a major role in the metastasis related www.selleckchem.com/products/Bosutinib.html behavior irrespective of the HGF status.