Polyploid tumour cells elicit paradiploid progeny through depolyploidizing divisions and regulated autophagic degradation
Polyploid tumour cells elicit paradiploid progeny through depolyploidizing divisions and regulated autophagic degradation
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DOI：
10.1042/cbi20100762
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发表时间：
2011-07-01
影响因子：
3.9
通讯作者：
Anisimov, Alim P.
中科院分区：
文献类型：
--
作者：
Erenpreisa, Jekaterina;Salmina, Kristine;Anisimov, Alim P.
“Neosis”描述了 p53 功能缺陷的肿瘤细胞在基因毒性损伤后明显通过衰老的 ETC（内多倍体肿瘤细胞）进行自我更新的过程。我们之前报道过 ETC 中发生自噬消化和 DNA 挤出，随后发现自我更新转录因子在这些条件下也会被激活。在这里，我们进一步研究了伽马射线照射、ETO（依托泊苷）或 PXT（紫杉醇）治疗诱导的基因毒性损伤后一系列细胞系中的这种现象。这些实验表明，自噬导致的染色质降解与 ETC 中持续的有丝分裂活性相容。虽然在基因毒性损伤后早期产生的活跃多倍化初级 ETC 激活了整个多基因组的自我更新因子，但在多极有丝分裂失败后恢复的次级 ETC 经历了亚核分化。因此，只有一部分亚核继续表达 OCT4 和 NANOG，而那些缺乏这些因子的亚核则停止 DNA 复制，并通过自噬进行降解和消除。幸存的亚核隔离新生细胞质以形成亚细胞，同时保留在旧 ETC 的范围内。最后，预先形成的副二倍体亚细胞通过自噬从连接的染色体桥中释放出来，随后开始细胞分裂。这些数据表明，由基因毒性受损的 p53 功能缺陷肿瘤细胞产生的“新生”ETC 通过异核系统发育，将多倍体基因组分化为恢复活力的“存活”亚细胞（提供有丝分裂繁殖的副二倍体后代）和亚核，这些亚细胞通过自噬而降解和消除。整个过程减少了 ETC 后代的非整倍性。
'Neosis' describes the process whereby p53 function-deficient tumour cells undergo self-renewal after genotoxic damage apparently via senescing ETCs (endopolyploid tumour cells). We previously reported that autophagic digestion and extrusion of DNA occurs in ETC and subsequently revealed that self-renewal transcription factors are also activated under these conditions. Here, we further studied this phenomenon in a range of cell lines after genotoxic damage induced by gamma irradiation, ETO (etoposide) or PXT (paclitaxel) treatment. These experiments revealed that chromatin degradation by autophagy was compatible with continuing mitotic activity in ETC. While the actively polyploidizing primary ETC produced early after genotoxic insult activated self-renewal factors throughout the polygenome, the secondary ETC restored after failed multipolar mitosis underwent subnuclei differentiation. As such, only a subset of subnuclei continued to express OCT4 and NANOG, while those lacking these factors stopped DNA replication and underwent degradation and elimination through autophagy. The surviving subnuclei sequestered nascent cytoplasm to form subcells, while being retained within the confines of the old ETC. Finally, the preformed paradiploid subcells became released from their linking chromosome bridges through autophagy and subsequently began cell divisions. These data show that 'neotic' ETC resulting from genotoxically damaged p53 function-deficient tumour cells develop through a heteronuclear system differentiating the polyploid genome into rejuvenated 'viable' subcells (which provide mitotically propagating paradiploid descendents) and subnuclei, which become degraded and eliminated by autophagy. The whole process reduces aneuploidy in descendants of ETC.