汉防己甲素抑制胰腺癌细胞周期失调：对 p21、p27 和细胞周期蛋白 D1 的差异调节。
Tetrandrine inhibits deregulated cell cycle in pancreatic cancer cells: Differential regulation of p21, p27 and cyclin D1.
机构信息
Department of Biochemistry and Molecular Biology, LSU Health Sciences Center, 1501 Kings Highway, Shreveport, LA, 71130, USA; Feist Weiller Cancer Center, 1501 Kings Highway, Shreveport, LA, 71130, USA.
Department of Biochemistry and Molecular Biology, LSU Health Sciences Center, 1501 Kings Highway, Shreveport, LA, 71130, USA.
出版信息
Cancer Lett. 2018 Jul 1;425:164-173. doi: 10.1016/j.canlet.2018.03.042. Epub 2018 Mar 30.
Current therapies in Pancreatic Cancer (PaCa) are ineffective due to deregulated cell cycle driven by landscape mutations. In this study, we show for the first time that tetrandrine (TET) inhibits proliferation of the PaCa cells and inhibits PaCa tumor growth. TET inhibits cell cycle transition at G1/S boundary. TET increased levels of p21 and p27, had no effect on the levels of CDK4/6 proteins and decreased the levels of cyclin D1 and pRb proteins. TET resulted in changes in mRNA levels of cyclin D1 and p21 but had no effect on the mRNA of p27. We show, for the first time in any system, that TET treatment downregulated Skp2, E3 ligase specific for degradation of p27 during the cell cycle. Taken together our results show, that TET indirectly impairs the activities of CDK4/6 to halt deregulated cell cycle and inhibit PaCa tumor growth. These results suggest that TET may serve as a novel agent for treatment of PaCa, for which there is no effective cure to date.
由于受景观突变驱动的细胞周期失调，目前胰腺癌（PaCa）的治疗方法均无效。在这项研究中，我们首次表明汉防己甲素（TET）可抑制 PaCa 细胞的增殖并抑制 PaCa 肿瘤的生长。TET 可抑制 G1/S 边界的细胞周期转换。TET 增加了 p21 和 p27 的水平，对 CDK4/6 蛋白水平没有影响，降低了 cyclin D1 和 pRb 蛋白的水平。TET 导致 cyclin D1 和 p21 的 mRNA 水平发生变化，但对 p27 的 mRNA 没有影响。我们首次在任何系统中表明，TET 处理可下调 Skp2，Skp2 是细胞周期中降解 p27 的 E3 连接酶的特异性蛋白。综上所述，我们的研究结果表明，TET 可间接削弱 CDK4/6 的活性，从而阻止失调的细胞周期并抑制 PaCa 肿瘤的生长。这些结果表明，TET 可能成为治疗 PaCa 的新型药物，目前尚无有效的治疗方法。
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