Vora Shivam, Chatterjee Saptarshi, Andrew Ariel, Kumar Ramyashree Prasanna, Proctor Martina, Zeng Zhen, Bhatt Rituparna, Nazareth Deborah, Fernando Madushan, Jones Mathew J K, He Yaowu, Hooper John D, McMillan Nigel A J, Urosevic Jelena, Saeh Jamal, Travers Jon, Cimini Daniela, Chen Jing, Gabrielli Brian
Mater Research Institute, The University of Queensland, Brisbane, QLD, Australia.
Department of Biological Sciences and Fralin Life Sciences Institute, Virginia Tech, Blacksburg, USA.
Cell Death Dis. 2025 Jan 8;16(1):7. doi: 10.1038/s41419-024-07329-7.
Polyploidy is a common outcome of chemotherapies, but there is conflicting evidence as to whether polyploidy is an adverse, benign or even favourable outcome. We show Aurora B kinase inhibitors efficiently promote polyploidy in many cell types, resulting in the cell cycle exit in RB and p53 functional cells, but hyper-polyploidy in cells with loss of RB and p53 function. These hyper-polyploid cells (>8n DNA content) are viable but have lost long-term proliferative potential in vitro and fail to form tumours in vivo. Investigation of mitosis in these cells revealed high numbers of centrosomes that were capable of supporting functional mitotic spindle poles, but these failed to progress to anaphase/telophase structures even when AURKB inhibitor was removed after 2-3 days. However, when AURKB inhibitor was removed after 1 day and cells had failed a single cytokinesis to become tetraploid, they retained colony forming ability and long-term proliferative potential. Mathematical modelling of the potential for polyploid cells to produce viable daughter cells demonstrated that cells with >8n DNA and >4 functional spindle poles approach zero probability of a viable daughter, supporting our experimental observations. These findings demonstrate that tetraploidy is tolerated by tumour cells, but higher ploidy states are incompatible with long-term proliferative potential. Model for AURKBi driven hyper-polyploid cells formation and fate. Aurora B inhibitor (AURKBi) treatment of RB+p53 defective cells efficiently promotes failed cell division. One failed cell division produces three possible outcomes, continued proliferation of the tetraploid daughter, cell death, or if AURKBi is continued, high polyploid states. Once cell have failed cell division >twice and have >8n DNA content they will continue to undergo rounds of endomitosis even in the absence of AURKBi to either become viable hyper-polyploid or die. The hyper-polyploid cells have no long-term proliferative potential.
多倍体是化疗常见的结果，但关于多倍体是不良、良性甚至有利的结果，证据存在冲突。我们发现，极光激酶B（Aurora B）抑制剂能在多种细胞类型中有效促进多倍体形成，导致RB和p53功能正常的细胞退出细胞周期，但在RB和p53功能缺失的细胞中则导致超多倍体形成。这些超多倍体细胞（DNA含量>8n）是有活力的，但在体外失去了长期增殖潜力，在体内也无法形成肿瘤。对这些细胞有丝分裂的研究发现，它们有大量能够支持功能性有丝分裂纺锤体极的中心体，但即使在2 - 3天后去除AURKB抑制剂，这些中心体也无法进展到后期/末期结构。然而，当在1天后去除AURKB抑制剂且细胞未能通过一次胞质分裂成为四倍体时，它们保留了集落形成能力和长期增殖潜力。对多倍体细胞产生有活力子细胞可能性的数学建模表明，DNA含量>8n且有>4个功能性纺锤体极的细胞产生有活力子细胞的概率接近零，这支持了我们的实验观察结果。这些发现表明，肿瘤细胞能耐受四倍体，但更高的倍性状态与长期增殖潜力不兼容。AURKB抑制剂驱动超多倍体细胞形成及命运的模型。用极光激酶B抑制剂（AURKBi）处理RB + p53缺陷细胞可有效促进细胞分裂失败。一次细胞分裂失败会产生三种可能结果：四倍体子代细胞继续增殖、细胞死亡，或者如果继续使用AURKBi，则形成高倍性状态。一旦细胞分裂失败>两次且DNA含量>8n，即使在没有AURKBi的情况下，它们也会继续进行多轮核内复制，要么成为有活力的超多倍体，要么死亡。超多倍体细胞没有长期增殖潜力。
