PD0332991在套细胞淋巴瘤细胞集落形成中的作用

The role of PD0332991 in clonogenicity of mantle cell lymphoma cells

    摘要
  • 摘要:
      目的  探讨细胞周期蛋白依赖性激酶4/6（cyclin-dependent kinases 4/6，CDK4/6）靶向抑制剂PD0332991在套细胞淋巴瘤（mantle cell lymphoma，MCL）集落形成中的作用及机制。
      方法  采用流式细胞术检测PD0332991对MCL细胞周期的影响；应用Western blot法检测PD0332991处理后MCL细胞Rb蛋白和磷酸化Rb（phosphorylated retinal blastoma，p-Rb）蛋白的表达水平；采用集落形成实验检测PD0332991、米托蒽醌及双药联合对MCL细胞集落形成能力的影响。
      结果  采用流式细胞术研究证实PD0332991使G0/G1期MCL细胞明显增多，而S期细胞明显下降，导致细胞的G0/G1期阻滞。应用Western blot法检测显示PD0332991对Rb蛋白表达无影响，但能明显下调磷酸化Rb蛋白的水平。集落形成实验显示PD0332991可抑制MCL细胞集落形成，并增强米托蒽醌对MCL集落形成的抑制作用。
      结论  CDK4/6靶向抑制剂PD0332991可通过抑制MCL细胞Rb蛋白磷酸化，导致细胞的G0/G1期阻滞，增强米托蒽醌抑制MCL集落形成的能力。

     

    Abstract:
      Objective  To investigate the function and mechanism of cyclin-dependent kinase 4/6 (CDK4/6) inhibitor PD0332991 on clonogenicity of mantle cell lymphoma (MCL) cells.
      Methods  The effect of PD0332991 on MCL cell cycle distribution was assessed by flow cytometry; Western blot was used to test expression level of Rb protein and phosphorylated Rb protein in MCL after treatment with PD0332991; colony forming assay was performed to test the role of PD0332991 and mitoxantrone and their combination on colony forming activity in MCL.
      Results  Flow cytometry revealed that PD0332991 can increase G0/G1 phase MCL cells and significantly decrease S phase cells, leading to G0/G1 cell arrest. Western blot confirmed that PD0332991 exerted no effect on Rb protein expression but suppressed levels of phosphorylated Rb protein. Colony forming assay showed that PD0332991 significantly suppressed colony formation and enhanced the effect of mitoxantrone on colony forming activity in MCL.
      Conclusion  This study revealed that CDK4/6 inhibitor PD0332991 induced G0/G1 cell arrest and increased the effect of mitoxantrone on MCL clonogenicity by suppressing levels of phosphorylated Rb protein.

     

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