Activation of TGF- β - SMAD2 signaling by IL-6 drives neuroendocrine differentiation of prostate cancer through p38MAPK

In this study, PCa cells were differentiated with IL-6 in in-vitro to identify novel targets or signaling pathways associated with emergence of NEPC on deprivation of androgens. From the results, we observed an activation of TGF-β signaling pathway is altered through multiple proteins in differentiated LNCaP cells. Hence, we investigated the role of TGF-β axis in PCa cells differentiation. LNCaP cells treated with IL-6 in androgens deprived media release excess TGF-β ligand and this as conditioned media added to cells stimulated NED of PCa cells. TGF-β released by IL-6 stimulated cells activate p38MAPK through SMAD2 thereby promote NED. Inhibition of TGF-βRI and TGF-βRII signaling activation in LNCaP cells treated with IL-6 did not reversed the NED of cells, possibly due to the reason that the inhibition of TGF-β axis is further activating p38MAPK through SMAD independent manner in PCa cells. However, siRNA mediated knock down or inhibition p38MAPK inactivated TGF-β - SMAD axis in differentiating cells and attenuated NED of LNCaP cells. This result suggests that p38MAPK is the central node for receiving IL-6 signals and promotes NED of LNCaP cells in androgens free media. Remarkably, downregulation or inhibition of p38MAPK in NCI-H660 reversed NED characteristics as well as markers along with inactivation of SMAD2 whereas no effect observed in WPMY-1 normal prostate cells. Taken together these findings unveil that p38MAPK and its upstream regulators are potential targ...
Source: Cellular Signalling - Category: Cytology Authors: Source Type: research