Prostate cancer (PCa) frequently metastasizes to the bone leading to devastating complications such as severe pain and fracture. However, the mechanisms by which PCa cells cause bone loss remain less understood. We investigated the role and mechanisms by which PCa cells induce osteoclastogenesis using cultured monocytic osteoclast precursors. Treatment of RAW264.7 cells with PCa cell lines: DU145, LNCaP, PC‐3, or their conditioned media led to the formation of distinct multinucleated, TRAP⁺ osteoclasts. This phenomenon was associated with the increased activation of transcription factor nuclear factor‐kB (NF‐κB). High transcript level of receptor activator of nuclear factor‐kB ligand (RANKL), tumor necrosis factor‐α (TNF‐α), and interleukin‐6 (IL‐6) were detected in PCa cells. TNF‐α and LT‐α augmented, whereas IL‐6 reduced the RANKL‐induced osteoclast formation in RAW264.7 cultures. Our results also demonstrated that PCa cells‐induced osteoclastogenesis involved the activation of the TRAF6–IKK–p65–NF‐κB signaling cascade. Together, our study demonstrates that PCa cells produce RANKL and several other pro‐inflammatory cytokines known to influence osteoclastogenesis, by targeting the NF‐κB signaling pathway.

中文翻译：

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NF-κB 和相互作用细胞因子在前列腺癌诱导的破骨细胞生成过程中的作用

前列腺癌 (PCa) 经常转移到骨骼，导致严重的疼痛和骨折等严重并发症。然而，PCa 细胞导致骨质流失的机制仍然知之甚少。我们研究了 PCa 细胞使用培养的单核细胞破骨细胞前体诱导破骨细胞生成的作用和机制。用 PCa 细胞系处理 RAW264.7 细胞：DU145、LNCaP、PC-3 或其条件培养基导致形成不同的多核、TRAP ⁺破骨细胞。这种现象与转录因子核因子-k B (NF-κB) 的激活增加有关。核因子-k受体激活剂的高转录水平在PCa细胞中检测到B配体（RANKL）、肿瘤坏死因子-α（TNF-α）和白细胞介素-6（IL-6）。TNF-α 和 LT-α 增加，而 IL-6 减少了 RAW264.7 培养物中 RANKL 诱导的破骨细胞形成。我们的结果还表明，PCa 细胞诱导的破骨细胞生成涉及 TRAF6-IKK-p65-NF-κB 信号级联的激活。总之，我们的研究表明，PCa 细胞通过靶向 NF-κB 信号通路产生 RANKL 和其他几种已知影响破骨细胞生成的促炎细胞因子。