Dinaciclib, a cyclin-dependent kinase-5 (CDK5) inhibitor, has significant anti-tumor properties. However, the precise mechanism of dinaciclib requires further investigation. Herein, we investigated the anti-tumor functions and molecular basis of dinaciclib in pancreatic ductal adenocarcinoma (PDAC). PDAC and matched para-carcinoma specimens were collected from the patients who underwent radical resection. Immunohistochemistry was performed to assess CDK5 expression. Cell proliferation ability, migration, and invasion were measured using Cell Counting Kit-8, wound healing, and transwell assay, respectively. The cell cycle and apoptosis were assessed using flow cytometry. Gene expression was examined using RNA-seq and quantitative real-time PCR. Protein expression of proteins was measured by western blot analysis and immunofluorescence microscopy. Tumor-bearing mice were intraperitoneally injected with dinaciclib. CDK5 is highly expressed in PDAC. The expression level of CDK5 was significantly related to tumor size, T stage, and the American Joint Committee on Cancer stage. High CDK5 expression can predict poor survival in PDAC patients. In addition, the expression level of CDK5 might be an independent prognostic factor for PDAC patients. Dinaciclib inhibits the growth and motility of PDAC cells and induces apoptosis and cell cycle arrest in the G2/M phase. Mechanistically, dinaciclib down-regulated yes-associated protein (YAP) mRNA and protein expression by reducing β-catenin expression. Moreover, dinaciclib significantly inhibited PDAC cell growth in vivo. Our findings reveal a novel anti-tumor mechanism of dinaciclib in which it decreases YAP expression by down-regulating β-catenin at the transcriptional level rather than by activating Hippo pathway-mediated phosphorylation-dependent degradation.

中文翻译：

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Dinaciclib 通过 β-catenin/YAP 轴在胰腺导管腺癌中发挥肿瘤抑制作用。

Dinaciclib 是一种细胞周期蛋白依赖性激酶 5 (CDK5) 抑制剂，具有显着的抗肿瘤特性。然而，dinaciclib 的确切机制还需要进一步研究。在此，我们研究了 dinaciclib 在胰腺导管腺癌（PDAC）中的抗肿瘤功能和分子基础。从接受根治性切除的患者中收集 PDAC 和匹配的癌旁标本。进行免疫组织化学以评估CDK5表达。分别使用Cell Counting Kit-8、伤口愈合和transwell实验测量细胞增殖能力、迁移能力和侵袭能力。使用流式细胞术评估细胞周期和细胞凋亡。使用 RNA-seq 和定量实时 PCR 检查基因表达。通过蛋白质印迹分析和免疫荧光显微镜测量蛋白质的蛋白质表达。荷瘤小鼠腹腔注射 dinaciclib。CDK5 在 PDAC 中高表达。CDK5的表达水平与肿瘤大小、T分期、美国癌症联合委员会分期显着相关。CDK5 高表达可以预测 PDAC 患者的生存率较差。此外，CDK5的表达水平可能是PDAC患者的独立预后因素。Dinaciclib 抑制 PDAC 细胞的生长和运动，并诱导细胞凋亡和细胞周期停滞在 G2/M 期。从机制上讲，dinaciclib 通过减少 β-catenin 表达来下调 yes 相关蛋白 (YAP) mRNA 和蛋白表达。此外，dinaciclib 显着抑制体内 PDAC 细胞生长。我们的研究结果揭示了 dinaciclib 的一种新的抗肿瘤机制，其中它通过在转录水平下调 β-catenin 来降低 YAP 表达，而不是通过激活 Hippo 途径介导的磷酸化依赖性降解。