Neuroendocrine Prostate Cancer (NEPC) is an aggressive form of androgen independent prostate cancer (AIPC), correlated with therapeutic resistance. Interleukin (IL)-6 promotes proliferation and neuroendocrine differentiation (NED) of androgen dependent LNCaP cells. We treated LNCaP cells with IL-6 and observed for in vitro NED of cells and also expression of NE markers βIII tubulin, neuron-specific enolase (NSE) and chromogranin A (ChA). Here we investigated the proteins and/or pathways involved in NED of LNCaP cells induced by IL-6 and characterized their role in NED of PCa cells. We found that the altered proteins modulated AMPK signaling pathway in NE cells. Remarkably, IL-6 induces NED of LNCaP cells through activation of AMPK and SIRT1 and also both of these are co-regulated while playing a predominant role in NED of LNCaP cells. Of the few requirements of AMPK-SIRT1 activation, increased eNOS is essential for NED by elevating Nitric oxide (NO) levels. Pleiotropic effects of NO ultimately regulate p38MAPK in IL-6 induced NED. Hence, IL-6 induced AMPK-SIRT1 activation eventually transfers its activation signals through p38MAPK for advancing NED of LNCaP cells. Moreover, inactivation of p38MAPK with specific inhibitor (SB203580) attenuated IL-6 induced NED of LNCaP cells. Therefore, IL-6 promotes NED of PCa cells via AMPK/SIRT1/p38MAPK signaling. Finally, targeting AMPK-SIRT1 or p38MAPK in androgen independent PC3 cells with neuroendocrine features reversed their neuroendocrine characteristics. Taken together these novel findings reveal that targeting p38MAPK mitigated NED of PCa cells, and thus it can be a favorable target to overcome progression of NEPC.

神经内分泌前列腺癌 (NEPC) 是雄激素非依赖性前列腺癌 (AIPC) 的一种侵袭性形式，与治疗抵抗相关。白细胞介素 (IL)-6 促进雄激素依赖性 LNCaP 细胞的增殖和神经内分泌分化 (NED)。我们用 IL-6 处理 LNCaP 细胞并在体外观察细胞的 NED 以及 NE 标记物 βIII 微管蛋白、神经元特异性烯醇化酶 (NSE) 和嗜铬粒蛋白 A (ChA) 的表达。在这里，我们研究了 IL-6 诱导的 LNCaP 细胞 NED 中涉及的蛋白质和/或途径，并表征了它们在 PCa 细胞 NED 中的作用。我们发现改变的蛋白质调节了 NE 细胞中的 AMPK 信号通路。值得注意的是，IL-6 通过激活 AMPK 和 SIRT1 诱导 LNCaP 细胞的 NED，并且这两者在 LNCaP 细胞的 NED 中起主要作用的同时被共同调节。在 AMPK-SIRT1 激活的少数要求中，增加的 eNOS 通过提高一氧化氮 (NO) 水平对 NED 至关重要。NO 的多效作用最终在 IL-6 诱导的 NED 中调节 p38MAPK。因此，IL-6 诱导的 AMPK-SIRT1 激活最终通过 p38MAPK 传递其激活信号，以促进 LNCaP 细胞的 NED。此外，用特异性抑制剂 (SB203580) 灭活 p38MAPK 减弱了 IL-6 诱导的 LNCaP 细胞的 NED。因此，IL-6 促进 PCa 细胞的 NED通过AMPK/SIRT1/p38MAPK 信号。最后，在具有神经内分泌特征的雄激素非依赖性 PC3 细胞中靶向 AMPK-SIRT1 或 p38MAPK 逆转了它们的神经内分泌特征。综上所述，这些新发现表明靶向 p38MAPK 减轻了 PCa 细胞的 NED，因此它可能是克服 NEPC 进展的有利目标。