Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania; Amity Institute of Molecular Medicine and Stem Cell Research, Amity University, Noida, India.
Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania.
Am J Pathol. 2023 May;193(5):624-637. doi: 10.1016/j.ajpath.2023.01.004. Epub 2023 Feb 3.
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 metastasis in 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.
晚期前列腺肿瘤转移到骨骼，常导致死亡。蛋白激酶 D (PKD) 家族已被牵连到前列腺癌的发展；然而，其在前列腺癌转移中的作用仍不清楚。本研究检查了 PKD，特别是 PKD2 和 PKD3（PKD2/3），对前列腺癌细胞转移潜能的贡献，以及 PKD 抑制对体内前列腺癌骨转移的影响。siRNA 敲低 PKD2/3 或 PKD 抑制剂 CRT0066101 抑制 AR 阳性和 AR 阴性去势抵抗性前列腺癌细胞中的 PKD2/3，强烈抑制集落形成和细胞迁移。PKD2/3 的敲低或抑制显著阻断肿瘤细胞侵袭，并抑制高度侵袭性 PC3-ML 细胞中与骨转移相关的基因表达。PKD2/3 敲低导致的侵袭活性降低部分是由转录因子 Runx2 介导的，因为其沉默通过丝裂原活化蛋白激酶激酶/细胞外信号调节激酶 1/2 信号通路降低了 PKD2/3 介导的转移基因表达。此外，CRT0066101 抑制 PKD 强烈降低了基于 PC3-ML 细胞心内注射的骨转移小鼠模型中的骨微转移频率。这些结果表明 PKD2/3 在前列腺癌细胞的骨转移中发挥重要作用，其抑制可能有益于晚期前列腺癌的治疗。
