Polyploid tumour cells elicit paradiploid progeny through depolyploidizing divisions and regulated autophagic degradation.
'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.
Latvian Biomedical Centre, Ratsupites 1, Riga, Latvia. katrina@biomed.lu.lv
Jekaterina
J
Erenpreisa
Kristine
K
Salmina
Anda
A
Huna
Elizabeth A
EA
Kosmacek
Mark S
MS
Cragg
Fiorenza
F
Ianzini
Alim P
AP
Anisimov
D001343:Autophagy / Q000187:drug effects / Q000528:radiation effects; D045744:Cell Line, Tumor; D002843:Chromatin / Q000235:genetics / Q000378:metabolism*; D042002:Chromatin Assembly and Disassembly; D053938:DNA Fragmentation / Q000187:drug effects / Q000528:radiation effects; D004261:DNA Replication / Q000187:drug effects / Q000528:radiation effects; D005047:Etoposide / Q000494:pharmacology; D005720:Gamma Rays / Q000009:adverse effects; D015894:Genome, Human; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008938:Mitosis; D000071317:Nanog Homeobox Protein; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D050814:Octamer Transcription Factor-3 / Q000235:genetics / Q000378:metabolism; D017239:Paclitaxel / Q000494:pharmacology; D011003:Ploidies; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency* / Q000235:genetics
D002843:Chromatin; D018398:Homeodomain Proteins; C486780:NANOG protein, human; D000071317:Nanog Homeobox Protein; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; D016159:Tumor Suppressor Protein p53; D005047:Etoposide; D017239:Paclitaxel