Protein Kinase D2 and D3 Promote Prostate Cancer Cell Bone Metastasis by Positively Regulating Runx2 in a MEK/ERK1/2-Dependent Manner.
Protein Kinase D2 and D3 Promote Prostate Cancer Cell Bone Metastasis by Positively Regulating Runx2 in a MEK/ERK1/2-Dependent Manner.
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蛋白激酶 D2 和 D3 通过以 MEK/ERK1/2 依赖性方式正向调节 Runx2 促进前列腺癌细胞骨转移。
DOI：
10.1016/j.ajpath.2023.01.004
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Wang,QimingJane
中科院分区：
文献类型：
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作者：
Roy,Adhiraj;Prasad,Sahdeo;Chen,Yuzhou;Chao,Yapeng;Liu,Yu;Zhao,Jinjun;Wang,QimingJane
晚期前列腺肿瘤转移到骨骼，常常导致死亡。蛋白激酶D （PKD）家族与前列腺癌的发展有关；然而，其在前列腺癌转移中的作用尚不明确。本研究探讨了PKD，特别是PKD2和PKD3 （PKD2/3）在前列腺癌细胞转移潜能中的作用，以及PKD抑制对前列腺癌骨转移的影响。在ar阳性和ar阴性的去势抵抗前列腺癌细胞中，sirna对PKD2/3的消耗或PKD抑制剂CRT0066101的抑制能有效地抑制集落形成和细胞迁移。在高侵袭性PC3-ML细胞中，缺失或抑制PKD2/3可显著阻断肿瘤细胞的侵袭，抑制骨转移相关基因的表达。PKD2/3缺失导致的侵袭活性降低部分是由转录因子Runx2介导的，因为它的沉默降低了PKD2/3通过丝裂原激活的蛋白激酶激酶/细胞外信号调节的激酶1/2信号轴介导的转移基因表达。此外，在基于心内注射PC3-ML细胞的骨转移小鼠模型中，CRT0066101对PKD的抑制有效地降低了骨微转移的频率。这些结果提示PKD2/3在前列腺癌细胞骨转移中起重要作用，抑制其表达可能有利于晚期前列腺癌的治疗。
Advanced-stage prostate tumors metastasize to the bone, often causing death. The protein kinase D (PKD) family has been implicated in prostate cancer development; however, its role in prostate cancer metastasis remains elusive. This study examined the contribution of PKD, particularly PKD2 and PKD3 (PKD2/3), to the metastatic potential of prostate cancer cells and the effect of PKD inhibition on prostate cancer bone metastasisin vivo. Depletion of PKD2/3 by siRNAs or inhibition by the PKD inhibitor CRT0066101 in AR-positive and AR-negative castration-resistant prostate cancer cells potently inhibited colony formation and cell migration. Depletion or inhibition of PKD2/3 significantly blocked tumor cell invasion and suppressed the expression of genes related to bone metastasis in the highly invasive PC3-ML cells. The reduced invasive activity resulting from PKD2/3 depletion was in part mediated by the transcription factor Runx2, as its silencing decreased PKD2/3–mediated metastatic gene expression through the mitogen-activated protein kinase kinase/extracellular signal–regulated kinase 1/2 signaling axis. Furthermore, inhibition of PKD by CRT0066101 potently decreased the frequency of bone micrometastases in a mouse model of bone metastasis based on intracardiac injection of PC3-ML cells. These results indicate that PKD2/3 plays an important role in the bone metastasis of prostate cancer cells, and its inhibition may be beneficial for the treatment of advanced prostate cancer.