Prostate cancer-secreted CCN3 uses the GSK3β and β-catenin pathways to enhance osteogenic factor levels in osteoblasts
Prostate cancer-secreted CCN3 uses the GSK3β and β-catenin pathways to enhance osteogenic factor levels in osteoblasts
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DOI：
10.1002/tox.23048
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发表时间：
2020-10-27
影响因子：
4.5
通讯作者：
Tang, Chih-Hsin
中科院分区：
文献类型：
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作者：
Chen, Po-Chun;Liu, Shan-Chi;Tang, Chih-Hsin
前列腺癌成骨细胞骨转移是不可治愈的，并伴有慢性骨痛和高死亡率。旨在预防前列腺癌骨转移相关的泌尿系相关事件的破骨细胞靶向药物不会延长总生存期。需要进一步了解导致前列腺癌成骨细胞骨转移的骨源性因素，以设计改善发病率和总生存率的治疗方法。活化的成骨细胞刺激前列腺癌在骨中生长。在这项研究中，我们报告了前列腺癌条件培养基（CM）促进成骨细胞中骨形态发生蛋白（BMP）-2，4和-7的产生以及成骨转录因子Runx 2和osterix的表达。用CCN 3（肾母细胞瘤过度表达）抗体治疗前列腺癌CM，CCN 3是一种富含半胱氨酸的蛋白质，属于CCN家族，减少了所有这些增加。用CCN 3孵育成骨细胞促进GSK 3 β和β-连环蛋白的磷酸化。GSK 3 β和β-连环蛋白抑制剂或siRNA都消除了CCN 3诱导的成骨细胞中BMP、Runx 2和osterix表达的促进作用。我们的研究结果表明，前列腺癌分泌的CCN 3通过GSK 3 β和β-连环蛋白信号通路增强成骨细胞中BMP、Runx 2和osterix的表达。这种对CCN 3在成骨前列腺骨转移中所起作用的理解可能会导致更有效的靶向治疗。
Prostate cancer osteoblastic bone metastases are incurable and associated with chronic bone pain and a high mortality rate. Osteoclast-targeting drugs intended to prevent skeletal-related events associated with prostate cancer bone metastases do not prolong overall survival. Improved understanding of the bone-derived factors that contribute to prostate cancer osteoblastic bone metastases is required to design treatments that will improve morbidities and overall survival. Activated osteoblasts stimulate prostate cancer growth in bone. In this study, we report that prostate cancer conditioned medium (CM) promoted bone morphogenetic protein (BMP)-2, -4 and -7 production and the expression of osteogenic transcription factors Runx2 and osterix in osteoblasts. Treating the prostate cancer CM with antibody against CCN3 (nephroblastoma-overexpressed), a cysteine-rich protein that belongs to the CCN family, reduced all of these increases. Incubation of osteoblasts with CCN3 facilitated phosphorylation of GSK3 beta and beta-catenin. GSK3 beta and beta-catenin inhibitors or siRNAs all abolished CCN3-induced promotion of BMPs, Runx2 and osterix expression in osteoblasts. Our results indicate that prostate cancer-secreted CCN3 enhances BMP, Runx2 and osterix expression in osteoblasts via the GSK3 beta and beta-catenin signaling pathways. This understanding of the role played by CCN3 in osteoblastic prostate bone metastasis may lead to more efficient targeted therapies.