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

Neuroendocrine prostate cancer (NEPC) is an aggressive, androgen independent PCa and it is detected in patients undergoing androgen deprivation therapy (ADT). Interleukin-6 (IL-6) is a pleiotropic cytokine elevated in PCa patients promotes neuroendocrine differentiation (NED). 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-beta signaling pathway is altered through multiple proteins in differentiated LNCaP cells. Hence, we investigated the role of TGF-beta axis in PCa cells differentiation. LNCaP cells treated with IL-6 in androgens deprived media release excess TGF-beta ligand and this as conditioned media added to cells stimulated NED of PCa cells. TGF-beta released by IL-6 stimulated cells activate p38MAPK through SMAD2 thereby promote NED. Inhibition of TGF-beta RI and TGF-beta RII 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-beta axis is further activating p38MAPK through SMAD independent manner in PCa cells. However, siRNA mediated knock down or inhibition p38MAPK inactivated TGF-beta - 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 targets to overcome the progression of NED of PCa and develop novel therapeutic measures along ADT for effective treatment of PCa.

Automated summary

Neuroendocrine prostate cancer (NEPC) is an aggressive form of prostate cancer that persists even without androgen hormones. This study reveals the role of interleukin-6 (IL-6) in promoting neuroendocrine differentiation (NED) in prostate cancer cells. The TGF-beta signaling pathway, specifically p38MAPK, is identified as the key regulator of IL-6-induced NED. These findings suggest that targeting p38MAPK and its upstream regulators could be a potential therapeutic strategy for treating NEPC.