Papanagnou Eleni-Dimitra, Terpos Evangelos, Kastritis Efstathios, Papassideri Issidora S, Tsitsilonis Ourania E, Dimopoulos Meletios A, Trougakos Ioannis P
Department of Cell Biology and Biophysics, Faculty of Biology, National and Kapodistrian University of Athens, 15784 Athens, Greece.
Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, 11528 Athens, Greece.
Oncotarget. 2018 Apr 3;9(25):17797-17809. doi: 10.18632/oncotarget.24882.
Proteasome is central to proteostasis network functionality and its over-activation represents a hallmark of advanced tumors; thus, its selective inhibition provides a strategy for the development of novel antitumor therapies. In support, proteasome inhibitors, e.g. Bortezomib or Carfilzomib have demonstrated clinical efficacy against hematological cancers. Herein, we studied proteasome regulation in peripheral blood mononuclear cells and erythrocytes isolated from healthy donors or from Multiple Myeloma patients treated with Bortezomib or Carfilzomib. In healthy donors we found that peripheral blood mononuclear cells express higher, as compared to erythrocytes, basal proteasome activities, as well as that proteasome activities decline during aging. Studies in cells isolated from Multiple Myeloma patients treated with proteasome inhibitors revealed that in most (but, interestingly enough, not all) patients, proteasome activities decline in both cell types during therapy. In peripheral blood mononuclear cells, most proteostatic genes expression patterns showed a positive correlation during therapy indicating that proteostasis network modules likely respond to proteasome inhibition as a functional unit. Finally, the expression levels of antioxidant, chaperone and aggresomes removal/autophagy genes were found to inversely associate with patients' survival. Our studies will support a more personalized therapeutic approach in hematological malignancies treated with proteasome inhibitors.
蛋白酶体对于蛋白质稳态网络功能至关重要，其过度激活是晚期肿瘤的一个标志；因此，对其进行选择性抑制为开发新型抗肿瘤疗法提供了一种策略。作为支持，蛋白酶体抑制剂，如硼替佐米或卡非佐米，已在治疗血液系统癌症方面显示出临床疗效。在此，我们研究了从健康供体或接受硼替佐米或卡非佐米治疗的多发性骨髓瘤患者中分离出的外周血单核细胞和红细胞中的蛋白酶体调节情况。在健康供体中，我们发现与红细胞相比，外周血单核细胞表达更高的基础蛋白酶体活性，并且蛋白酶体活性在衰老过程中会下降。对接受蛋白酶体抑制剂治疗的多发性骨髓瘤患者分离出的细胞进行的研究表明，在大多数（但有趣的是，并非所有）患者中，治疗期间两种细胞类型中的蛋白酶体活性都会下降。在外周血单核细胞中，大多数蛋白质稳态基因的表达模式在治疗期间呈正相关，这表明蛋白质稳态网络模块可能作为一个功能单元对蛋白酶体抑制做出反应。最后，发现抗氧化剂、伴侣蛋白和聚集体清除/自噬基因的表达水平与患者的生存率呈负相关。我们的研究将支持在用蛋白酶体抑制剂治疗血液系统恶性肿瘤时采用更个性化的治疗方法。
