Our current demonstration from the expression of Nodal and its receptors in prostate cancer cells and differential effects of Nodal on proliferation and migration of prostate cancer cells prompted us to review the biological effects of these two TGF superfamily members in prostate cells. Interestingly, Nodal and TGF exerted equivalent biological results on cell prolifer ation and migration which might be distinct to numerous prostate cell lines indicating that two cytokines might be able to substitute one another in prostate cancer progression. Therefore, any long term therapeutic tactics aimed at TGF loved ones will ought to take into consideration the overlapping roles of TGF B1 and Nodal while in distinct phases of prostate cancer. Comparable functions of Nodal and TGF in prostate cells prompted us to determine the variations in the intracellular signaling pathways employed by the two cytokines. Nodal and TGF receptors immediately activate Smad2 and or Smad3, nevertheless, Smad3 is shown to become the very important mediator of most Smad dependent TGF effects on gene expression, cell development, apoptosis and tumor suppression.
Alternatively, Smad2 only transmodulated Smad3 dependent transcrip tion suggesting that Smad2 and Smad3 have distinct roles in TGF signaling. We observed that TGF B1 stimulation led to pre dominantly Smad3 phosphorylation whereas Nodal induced generally Smad2 phosphorylation kinase inhibitor SB-715992 with minor, if any, effect on Smad3 phospho rylation in PZ HPV7, DU145 and PC3 cells. Moreover, a SIS3 also completely blocked TGF B1 results but had only small effects on Nodal signaling Raloxifene indicating that though Smad3 plays an critical role in TGF B1 signaling, Nodal results are exerted independent of Smad3 and presumably require only Smad2. Smad2 has proven to act as being a tumor suppressor during the basal epithelial or stem cell compartment of the prostate cells. Due to the fact Nodal maintains the pluripotency of human embryonic stem cells, it is feasible that Smad2 has a selective role in stem cell perform and involvement in Nodal signaling.
Our information propose that during the presence of Nodal and its receptors in prostate cancer cells, inhibition of TGF receptors and Smad3 alone could possibly not be sufficient to deal with innovative stages of prostate cancer. Preceding research have proven that Ski protein is overexpressed in human tumor cell lines and human tumor tissues from melanoma, breast, esophagus, cervical, colorectal, gastric and pancreatic cancers, but is weakly expressed in ordinary epithelial cells, mislocalization

and upregulation of Ski may perhaps contrib ute to malignant progression. Ski mRNA levels had been ubiq uitously expressed in all prostate cell lines within this study, having said that, increased levels of Ski protein have been observed in prostate cancer cells and prostate cancer tissue samples.