Cilibrasi Chiara, Guzzi Andrèe, Bazzoni Riccardo, Riva Gabriele, Cadamuro Massimiliano, Hochegger Helfrid, Bentivegna Angela
School of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy.
Ph.D. Program in Neuroscience, University of Milano-Bicocca, 20900 Monza, Italy.
J Oncol. 2019 Aug 19;2019:9014045. doi: 10.1155/2019/9014045. eCollection 2019.
Glioma stem cells account for glioblastoma relapse and resistance to conventional therapies, and protein kinases, involved in the regulation of the mitotic machinery (i.e., Aurora kinases), have recently emerged as attractive therapeutic targets. In this study, we investigated the effect of Aurora kinases inhibition in five glioma stem cell lines isolated from glioblastoma patients. As expected, cell lines responded to the loss of Aurora kinases with cytokinesis failure and mitotic exit without cell division. Surprisingly, this resulted in a proliferative arrest in only two of the five cell lines. These sensitive cell lines entered a senescent/autophagic state following aberrant mitotic exit, while the non-sensitive cell lines continued to proliferate. This senescence response did not correlate with TP53 mutation status but only occurred in the cell lines with the highest chromosome content. Repeated rounds of Aurora kinases inhibition caused a gradual increase in chromosome content in the resistant cell lines and eventually caused a similar senescence response and proliferative arrest. Our results suggest that a ploidy threshold is the main determinant of Aurora kinases sensitivity in TP53 mutant glioma stem cells. Thus, ploidy could be used as a biomarker for treating glioma patients with Aurora kinases inhibitors.
胶质瘤干细胞导致胶质母细胞瘤复发及对传统疗法产生耐药性，而参与有丝分裂机制调控的蛋白激酶（即极光激酶）最近已成为有吸引力的治疗靶点。在本研究中，我们调查了极光激酶抑制对从胶质母细胞瘤患者中分离出的5种胶质瘤干细胞系的影响。正如预期的那样，细胞系因极光激酶缺失而出现胞质分裂失败和有丝分裂退出但无细胞分裂。令人惊讶的是，这仅导致5种细胞系中的2种出现增殖停滞。这些敏感细胞系在异常有丝分裂退出后进入衰老/自噬状态，而非敏感细胞系则继续增殖。这种衰老反应与TP53突变状态无关，仅发生在染色体含量最高的细胞系中。重复进行多轮极光激酶抑制会导致耐药细胞系中的染色体含量逐渐增加，并最终引发类似的衰老反应和增殖停滞。我们的结果表明，倍性阈值是TP53突变型胶质瘤干细胞中极光激酶敏感性的主要决定因素。因此，倍性可作为使用极光激酶抑制剂治疗胶质瘤患者的生物标志物。
