Abstract
Accelerated senescence of cancer stem cells (CSCs) represents an adaptive response allowing withstand cell death. TP53, the pivotal tumor suppressor plays an important role in this process by inducing a prolonged dual state with senescence and self-renewal as potential outcomes. Molecularly, this is achieved by activating both OCT4A (POU5F1) and p21CIP1. OCT4A suppresses the excessive activity of p21 preventing the immediate precipitation of apoptosis or terminal senescence. It persists as long as sufficient cellular energy remains; generated through autophagy, itself sequestrating p16INK4A in the cytoplasm. As such, autophagic capacity is the bottleneck of these TP53-dependent senescence reversal processes, as well terminal senescence will follow if DNA damage is not ultimately repaired. In TP53 mutants the CSC-like state is boosted by stressed cells overcoming the tetraploidy barrier. These cells acquire additional DNA repair capacity through mitotic slippage and entrance to a sequence of ploidy cycles, allowing repair and sorting DNA damage, ultimately facilitating the genesis of mitotically competent daughter cells following final depolyploidisation. Again, autophagy is required to fuel this process. More detailed knowledge of these arcane processes anticipates the provision of anti-cancer drug targets, such as AURORA B kinase and Survivin, which ensure mitotic slippage and the continuity of ploidy cycles.
Keywords
- accelerated senescence
- cancer stem cells (CSCs)
- TP53
- DNA damage
- self-renewal OCT4A (POU5F1)
- p21CIP1
- pluripotency
- apoptosis
- metastability
- DNA repair
- autophagy
- p16INK4A
- tetraploidy
- ploidy cycles
- AURORA B
- Survivin
- AMPK
1. Introduction
In 2001 Roninson and colleagues [1] published the now seminal article entitled “If not apoptosis, then what? Treatment-induced senescence and mitotic catastrophe in tumor cells”. After decades of overwhelming attention toward apoptosis induction as the cure for cancer, this article gave birth to a new field in cancer research. They wrote: “Inhibition of the program of apoptosis has been reported to have little or no effect on clonogenic survival after treatment with drugs or radiation in several tumor cell lines. A decrease in apoptosis is compensated in such cell lines by an increase in the fractions of cells that undergo permanent growth arrest with phenotypic features of cell senescence. The senescent phenotype distinguishes tumor cells that survived drug exposure but lost the ability to form colonies from those that recover and proliferate after treatment. Although senescent cells do not proliferate, they are metabolically active and may produce secreted proteins with potential tumor-promoting activities.”
Since that article, the induction of senescence was even claimed as the new goal of cancer treatment [2] and many researchers stepped on this path.
In this chapter, we describe our data over the last 2 decades, which along with other research, substantiates the exact opposite: that so-called accelerated cell senescence (ASC) (also called stress-induced premature senescence) and mitotic catastrophe (MC) are not desired goals of cancer treatment. Rather, we show that these processes can enable genotoxically treated cancer cells to escape cell death, not only by secretion of survival promoting components [3] but also by effective DNA repair. By stabilizing or recovering the innate stem properties of cancer stem cells (CSCs) senescence can be reversed by DNA damaged-induced ACS. To explore these concepts clearly it is first important to review and define the typical features of cell senescence and the biology of CSCs.
2. Biological features of cell senescence: what is clear and what is not?
Replicative senescence is usually dependent on
3. The common biological features of embryonic stem cells (ESCs) and CSC
It is now generally accepted that CSCs play a central role in cancer genesis and promotion. Firstly, they possess the developmental potential, being capable of sphere formation and the ability to differentiate into mesoderm, endoderm and ectoderm progenies. Many gene modules of ESC are found active in various cancers [20], in turn, aggressive tumors express the markers of ESC or germ cells [21–24]. Third, tumors also acquire epigenetic profiles of ESC under genotoxic [25–28] or hypoxic conditions [29], in association with overcoming the tetraploidy barrier. So, epigenetically, CSCs of highly de-differentiated tumors possess many features of ESC.
Epigenetic instability is another notable feature of ESC and likely also of CSC. ESCs possess ‘poised’, chromatin marking of key developmental genes. Such marking consists of large regions of H3 lysine 27 methylation harboring smaller regions of H3 lysine 4 methylation. These domains tend to coincide with genes of transposable elements (TE) expressed at low levels [30]. Some activity of TE may provide the transcriptional noise, which is necessary for the fate changes observed during early embryo development [31, 32]. Moreover, the enhancers in ESCs are enriched for the transposable elements and genetic variations associated with cancer [33].
An additional peculiarity of ESC (and likewise CSC) is the absence of the cell cycle G1/S restriction checkpoint: here OCT4 and NANOG activate cyclin D kinases cdk4 and cdk6 [34] to force ESC into S-phase. Therefore, damaged ESC cells typically accumulate in the G2 DNA damage checkpoint instead, whose relative weakness allows mitotic slippage [35, 36]. Moreover, stressed ESC and likely also CSC possess a peculiar intermediate post-slippage phase (not 4 N-G1) [37, 38] containing non-degraded cyclin B1, which is normally destroyed after mitosis. In irradiated lymphomas and HeLa cells this nondegraded cyclin B1 was found to be sustained by activated Mos kinase [39]. Some additional activators of meiotic prophase were also revealed [40, 41] indicating a possible trigger from the mitotic DNA damage checkpoint into a meiotic prophase-like state with its more effective recombination checkpoint. Potentially, this meiosis-like molecular setting allows CSCs to tolerate both DNA damage and tetraploidy and use this compartment for DNA repair by homologous recombination [14, 42]. All three facets of CSC biology; poised chromatin, an epigenetic shift to embryonality, and the peculiar cell cycle checkpoints are apparently interrelated and involved in ACS, whose main hallmark is persistent DNA damage. The remainder of this chapter is an attempt to assess this notion within our experimental material.
4. Accelerated senescence of human fibroblasts induces senescing tetraploid cells with transient self-renewal potential
In one of our recent experimental systems, embryonal lung human fibroblasts (IMR90 cells) were grown in normoxia (20%) and 5% CO2 and reached full senescence (proliferative arrest with zero mitotic index) after 32–34 passages. Senescence was characterized by flat morphology of enlarged cells, nuclear positivity of p21CIP1 and cytoplasmic accumulation of p16INK4A; at the terminally stage nuclei were swelling and p16 entered the cell nuclei [43]. DNA cytometry revealed an accumulation of a portion of the prematurely senescing cells in the G2 compartment (Figure 1A, B) which were also overcoming the tetraploidy barrier with formation of a few (4–6%) tetraploid cells, which sometimes entered aberrant mitoses. These cells with large polyploid nuclei began to express both senescence markers (p21CIP1 and p16INK4A) with the self-renewal marker NANOG; these cells were also positive for DNA double strand breaks (DSB) (Figure 1C–F). The acquisition of bi-potentiality by a small proportion of normal cells overcoming the G2M DNA damage checkpoint is reminiscent of stem cell activity; with the same lack of arrest in the G1/S checkpoint and weak G2M checkpoint. Nevertheless, these cells did not persist in the culture and NANOG expression was lost in later passages.
These observations heightened our interest in the role of senescence in the CSC model.
5. Ovarian germline cells challenged by genotoxic stress display the dual p53-dependent expression of p21CIP1 and OCT4A
As a model for CSC we chose the ovarian germline cancer cells PA1. These cells are wt
Moreover, such stress-activated OCT4A was transiently disconnected from its self-renewal partners (SOX2 and NANOG), as those protein levels were low and/or not activated alongside Oct4A [46]. Therefore, the autoregulatory and feedforward loops seen in ESC [48] were not present, potentially due to the known down-regulation of the Nanog gene promoter by activated p53 [49] and/or the down-regulation of NANOG by high levels of OCT4A [50]. However, it is also possible that another, Cdk4-activating function of OCT4A [34] could be enhanced, while inhibiting action of p21on Cyclin D/cdk4,6 checkpoint function reduced forcing escape of the damaged cells from G1/S checkpoint leading to their accumulation in G2-arrest. Figure 3 presents these hypothetical relationships between the cell cycle and pluripotency functions of stress-activated OCT4A induced by DNA damage through activated p53.
The bizarre duality of OCT4A with p21CIP1 was subdued and cell cycle in the PA1 clones returned to normal, on days 7–14 (Figure 2A), while silencing of stress-activated OCT4A prevented recovery [46]. This transient undecided state in G2 arrest, between true senescence and true self-renewal, was thus lasting as long as wt
In accordance with our findings in PA1 cells after ETO treatment, a recent high-throughput RNAi screen revealed the intrinsic roles of S and G2, functionally establishing that pluripotency control is hardwired to the cell-cycle machinery and that the ATM/ATR-CHEK2-p53 axis enhances the TGF-b pathway to prevent premature cell death [36]. As well, [3] showed that cellular senescence accompanying DNA damage or DNA damage as such favors cell reprogramming in vivo models. It should be noted however, that the frequency (chance) of survival in our PA1-ETO model was not high. It stresses the importance of another possible player in this “undecided” stage between senescence and self-renewal, of transcriptional noise.
6. Transient bi-potentiality of CSC for senescence and self-renewal displays the population features of “noisy” expression and activated transposable elements
One of the interesting facets of this dual expression of self-renewal and senescence regulators in the PA1-ETO model was the high heterogeneity in response, with individual cells expressing wildly differing levels of OCT4 and p21 (Figure 4A). This explorative chaos continued for 4–6 days and culminated with massive cell death selecting a small proportion (<1%) of resistant survivors. Earlier studies on ESC observing the extensive heterogeneity and fluctuations of gene expression in individual stem cells led the authors to suggest that “noise “may be the central driving force behind multipotency [32, 50, 52].
Therefore, notably, a similar long ‘stochastic’ phase of choice between senescence and self-renewal (initiated by activating DNA repair and mesenchymal to epithelial transition), with heterogenous activation of pluripotency genes, preceding the period of further determination of self-renewal circuitry has also been reported during the induction of pluripotent stem cells [53].
Our study of DNA histograms in ETO-treated PA1 cells revealed in addition to G2M arrest, a strong under-replication in late S-phase (Figure 4B), the time of constitutive heterochromatin replication [46]. Similarly, arrest in late S- and G2M phase was reported after Doxorubicin treatment in p53 mutant cancer cells [54]. This feature may therefore be equally required for any senescence causing release from silencing and subsequent activation of TE nested in constitutive heterochromatin as retrotransposition was found in replicative cell senescence [55, 56]. In particular, under-replication may cause de-repression of TE genes and result in the epigenetic activation of the developmental genes in the poised chromatin regions [30] enabling the reprogramming by senescence. Indeed, we observed the activation and clustering of
7. The role of autophagy in preventing terminal senescence
Our further observations in the PA1 model showed the importance of autophagy in withstanding the proteotoxic stress following ETO treatment and its crucial role in maintaining viability; inhibition of autophagy culminated in chromatin fragmentation and nuclei disintegration [46, 57]. Stress-activated OCT4A mainly colocalized, and correlated in its nuclear concentration in individual cells, with activated AMPthr172 kinase (Figure 5A, B). AMP-activated protein kinase (AMPK) serves as a general energy depletion sensor and activator of autophagy. The energy stress-response of AMPK is also tightly linked to the DDR of p53 [58, 59] and can induce a p53-dependent glucose-sensitive metabolic checkpoint [51] precipitating apoptotic cell death from the G1/S and likely autophagic death from G2M checkpoint [60].
We found, in addition, that active autophagy in PA1-ETO cells sequestered p16INK4A aggresomes within the autophagic vacuoles (Figure 5C i–ii), while disability of autophagy enabled p16 diffuse distribution in the cell nuclei and caused terminal senescence with nuclear disintegration (Figure 5 iii-iv) preventing survival of ETO-treated cells [46]. The p53-dependent role of AMPK, its relationship with stress-activated OCT4A, and the role of autophagy in the prevention of terminal senescence for TP53 wild-type CSC cells is schematically presented in Figure 3.
However, in
8. TP53 mutants with persistent DNA damage undergo mitotic slippage, ploidy cycles, and are capable of reversing senescence alongside polyploidy
Some authors have reported that genotoxically treated cancer cells can paradoxically combine sa-β-gal-positivity (considered as a universal marker of senescence) with expression of Ki67, a hallmark signature of proliferation. This “swing phenotype” is apparently dependent on p21 and TERT [61]. Others have reported that sa-β-gal-positivity is also compatible with polylploid cells (induced by DNA chemotherapy) undergoing de-polyploidization and surviving [13, 16]. Overcoming the tetraploidy barrier in
All this indicates that
9. Acknowledgements
Mr. Jekabs Krigerts is acknowledged for formatting the article and illustrations.
References
- 1.
Roninson IB, Broude EV., Chang BD. If not apoptosis, then what? Treatment-induced senescence and mitotic catastrophe in tumor cells. Drug Resistance Updates. 2001; 4 (5):303-313. DOI: 10.1054/drup.2001.0213 - 2.
Shay JW, Roninson IB. Hallmarks of senescence in carcinogenesis and cancer therapy. Oncogene. 2004; 23 (16):2919-2933. DOI: 10.1038/sj.onc.1207518 - 3.
Mosteiro L, Pantoja C, Alcazar N, Marión RM, Chondronasiou D, Rovira M, et al. Tissue damage and senescence provide critical signals for cellular reprogramming in vivo. Science (80-). 2016; 354 (6315):aaf4445. DOI: 10.1126/science.aaf4445 - 4.
Collado M, Blasco MA, Serrano M. Cellular senescence in cancer and aging. Cell. 2007; 130 (2):223-233. DOI: 10.1016/j.cell.2007.07.003 - 5.
Suzuki M, Boothman DA. Stress-induced premature senescence (SIPS)–influence of SIPS on radiotherapy. Journal of Radiation Research. 2008; 49 (2):105-112 - 6.
d'Adda di Fagagna F. Living on a break: Cellular senescence as a DNA-damage response. Nature Reviews Cancer. 2008; 8 (7):512-522. DOI: 10.1038/nrc2440 - 7.
Rodier F, Coppé JP, Patil CK, Hoeijmakers WAM, Muñoz DP, Raza SR, et al. Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion. Nature Cell Biology. 2009; 11 (8):973-979. DOI: 10.1038/ncb1909 - 8.
Walen KH. Human diploid fibroblast cells in senescence; cycling through polyploidy to mitotic cells. In Vitro Cellular & Developmental Biology: Animal. 2006; 42 (7):216-224. DOI: 10.1290/0603019.1 - 9.
Mosieniak G, Sikora E. Polyploidy: The link between senescence and cancer. Current Pharmaceutical Design. 2010; 16 (6):734-740 - 10.
Mosieniak G, Sliwinska MA, Alster O, Strzeszewska A, Sunderland P, Piechota M, et al. Polyploidy formation in doxorubicin-treated cancer cells can favor escape from senescence. Neoplasia. 2015; 17 (12):882-893. DOI: 10.1016/j.neo.2015.11.008 - 11.
Sundaram M, Guernsey DL, Rajaraman MM, Rajaraman R. Neosis: A novel type of cell division in cancer. Cancer Biology and Therapy. 2004; 3 (2):207-218 - 12.
Tam WL, Ang YS, Lim B. The molecular basis of ageing in stem cells. Mechanisms of Ageing and Development. 2007; 128 (1):137-148. DOI: 10.1016/j.mad.2006.11.020 - 13.
Puig PE, Guilly MN, Bouchot A, Droin N, Cathelin D, Bouyer F, et al. Tumor cells can escape DNA-damaging cisplatin through DNA endoreduplication and reversible polyploidy. Cell Biology International. 2008; 32 (9):1031-1043. DOI: 10.1016/j.cellbi.2008.04.021 - 14.
Erenpreisa J, Cragg MS. Three steps to the immortality of cancer cells: Senescence, polyploidy and self-renewal. Cancer Cell International. 2013; 13 (1):92. DOI: 10.1186/1475-2867-13-92 - 15.
Wang Q, Wu PC, Dong DZ, Ivanova I, Chu E, Zeliadt S, et al. Polyploidy road to therapy-induced cellular senescence and escape. International Journal of Cancer. 2013; 132 (7):1505-1515. DOI: 10.1002/ijc.27810 - 16.
Sikora E, Mosieniak G, Sliwinska MA. Morphological and functional characteristic of senescent cancer cells. Current Drug Targets. 2016; 17 (4):377-387 - 17.
Sabisz M, Skladanowski A. Cancer stem cells and escape from drug-induced premature senescence in human lung tumor cells: Implications for drug resistance and in vitro drug screening models. Cell Cycle. 2009; 8 (19):3208-3217. DOI: 10.4161/cc.8.19.9758 - 18.
Chitikova Z V, Gordeev SA, Bykova TV, Zubova SG, Pospelov VA, Pospelova TV. Sustained activation of DNA damage response in irradiated apoptosis-resistant cells induces reversible senescence associated with mTOR downregulation and expression of stem cell markers. Cell Cycle. 2014; 13 (9):1424-1439. DOI: 10.4161/cc.28402 - 19.
Sharma S, Yao HP, Zhou YQ, Zhou J, Zhang R, Wang MH. Prevention of BMS-777607-induced polyploidy/senescence by mTOR inhibitor AZD8055 sensitizes breast cancer cells to cytotoxic chemotherapeutics. Molecular Oncology. 2014; 8 (3):469-482. DOI: 10.1016/j.molonc.2013.12.014 - 20.
Wong DJ, Liu H, Ridky TW, Cassarino D, Segal E, Chang HY. Module map of stem cell genes guides creation of epithelial cancer stem cells. Cell Stem Cell. 2008; 2 (4):333-344. DOI: 10.1016/j.stem.2008.02.009 - 21.
Old LJ. Cancer/testis (CT) antigens – A new link between gametogenesis and cancer. Cancer Immunity. 2001; 1 :1 - 22.
Kalejs M, Erenpreisa J. Cancer/testis antigens and gametogenesis: A review and “brain-storming” session. Cancer Cell International. 2005; 5 (1):4. DOI: 10.1186/1475-2867-5-4 - 23.
Kalejs M, Ivanov A, Plakhins G, Cragg MS, Emzinsh D, Illidge TM, et al. Upregulation of meiosis-specific genes in lymphoma cell lines following genotoxic insult and induction of mitotic catastrophe. BMC Cancer. 2006; 6 (1):6. DOI: 10.1186/1471-2407-6-6 - 24.
Ben-Porath I, Thomson MW, Carey VJ, Ge R, Bell GW, Regev A, et al. An embryonic stem cell-like gene expression signature in poorly differentiated aggressive human tumors. Nature Genetics. 2008; 40 (5):499-507. DOI: 10.1038/ng.127 - 25.
Salmina K, Jankevics E, Huna A, Perminov D, Radovica I, Klymenko T, et al. Up-regulation of the embryonic self-renewal network through reversible polyploidy in irradiated p53-mutant tumour cells. Experimental Cell Research. 2010; 316 (13):2099-2112. DOI: 10.1016/j.yexcr.2010.04.030 - 26.
Lagadec C, Vlashi E, Della Donna L, Dekmezian C, Pajonk F. Radiation-induced reprogramming of breast cancer cells. Stem Cells. 2012; 30 (5):833-844. DOI: 10.1002/stem.1058 - 27.
Vlashi E, Pajonk F. Cancer stem cells, cancer cell plasticity and radiation therapy. Seminars in Cancer Biology 2015; 31 :28-35. DOI: 10.1016/j.semcancer.2014.07.001 - 28.
Gerashchenko BI, Salmina K, Eglitis J, Huna A, Grjunberga V, Erenpreisa J. Disentangling the aneuploidy and senescence paradoxes: A study of triploid breast cancers non-responsive to neoadjuvant therapy. Histochemistry and Cell Biology. 2016; 145 (4):497-508. DOI: 10.1007/s00418-016-1415-x - 29.
Zhang S, Mercado-Uribe I, Xing Z, Sun B, Kuang J, Liu J. Generation of cancer stem-like cells through the formation of polyploid giant cancer cells. Oncogene. 2014; 33 (1):116-128. DOI: 10.1038/onc.2013.96 - 30.
Bernstein BE, Mikkelsen TS, Xie X, Kamal M, Huebert DJ, Cuff J, et al. A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell. 2006; 125 (2):315-326. DOI: 10.1016/j.cell.2006.02.041 - 31.
Peaston AE, Knowles BB, Hutchison KW. Genome plasticity in the mouse oocyte and early embryo. Biochemical Society Transactions. 2007; 35 (3):618-622. DOI: 10.1042/BST0350618 - 32.
Chang HH, Hemberg M, Barahona M, Ingber DE, Huang S. Transcriptome-wide noise controls lineage choice in mammalian progenitor cells. Nature. 2008; 453 (7194):544-547. DOI: 10.1038/nature06965 - 33.
Teng L, He B, Gao P, Gao L, Tan K. Discover context-specific combinatorial transcription factor interactions by integrating diverse ChIP-Seq data sets. Nucleic Acids Research. 2014; 42 (4):e24. DOI: 10.1093/nar/gkt1105 - 34.
Neganova I, Lako M. G1 to S phase cell cycle transition in somatic and embryonic stem cells. Journal of Anatomy. 2008; 213 (1):30-44. DOI: 10.1111/j.1469-7580.2008.00931.x - 35.
Boheler KR. Stem cell pluripotency: A cellular trait that depends on transcription factors, chromatin state and a checkpoint deficient cell cycle. Journal of Cellular Physiology. 2009; 221 (1):10-17. DOI: 10.1002/jcp.21866 - 36.
Gonzales KAU, Liang H, Lim YS, Chan YS, Yeo JC, Tan CP, et al. Deterministic restriction on pluripotent state dissolution by cell-cycle pathways. Cell. 2015; 162 (3):564-579. DOI: 10.1016/j.cell.2015.07.001 - 37.
Mantel C, Guo Y, Lee MR, Kim MK, Han MK, Shibayama H, et al. Checkpoint-apoptosis uncoupling in human and mouse embryonic stem cells: A source of karyotpic instability. Blood. 2007; 109 (10):4518-4527. DOI: 10.1182/blood-2006-10-054247 - 38.
Mantel C, Guo Y, Lee MR, Han MK, Rhorabough S, Kim KS, et al. Cells enter a unique intermediate 4 N stage, not 4 N-G1, after aborted mitosis. Cell Cycle. 2008; 7 (4):484-492. DOI: 10.4161/cc.7.4.5316 - 39.
Erenpreisa J, Kalejs M, Cragg M. Mitotic catastrophe and endomitosis in tumour cells: An evolutionary key to a molecular solution. Cell Biology International. 2005;29(12):1012-1018. DOI: 10.1016/j.cellbi.2005.10.005 - 40.
Ianzini F, Kosmacek EA, Nelson ES, Napoli E, Erenpreisa J, Kalejs M, et al. Activation of meiosis-specific genes is associated with depolyploidization of human tumor cells following radiation-induced mitotic catastrophe. Cancer Research. 2009; 69 (6):2296-2304. DOI: 10.1158/0008-5472.CAN-08-3364 - 41.
Erenpreisa J, Cragg MS, Salmina K, Hausmann M, Scherthan H. The role of meiotic cohesin REC8 in chromosome segregation in gamma irradiation-induced endopolyploid tumour cells. Experimental Cell Research. 2009; 315 (15):2593-2603. DOI: 10.1016/j.yexcr.2009.05.011 - 42.
Ivanov A, Cragg MS, Erenpreisa J, Emzinsh D, Lukman H, Illidge TM. Endopolyploid cells produced after severe genotoxic damage have the potential to repair DNA double strand breaks. Journal of Cell Science. 2003; 116 (20):4095-4106. DOI: 10.1242/jcs.00740 - 43.
Huna A, Salmina K, Jascenko E, Duburs G, Inashkina I, Erenpreisa J. Self-renewal signalling in presenescent tetraploid IMR90 cells. Journal of Aging Research 2011; 2011 :103253. DOI: 10.4061/2011/103253 - 44.
Lifantseva N, Koltsova A, Krylova T, Yakovleva T, Poljanskaya G, Gordeeva O. Expression patterns of cancer-testis antigens in human embryonic stem cells and their cell derivatives indicate lineage tracks. Stem Cells International 2011; 2011 :1-13. DOI: 10.4061/2011/795239 - 45.
Jackson TR, Salmina K, Huna A, Inashkina I, Jankevics E, Riekstina U, et al. DNA damage causes TP53-dependent coupling of self-renewal and senescence pathways in embryonal carcinoma cells. Cell Cycle. 2013; 12 (3):430-441. DOI: 10.4161/cc.23285 - 46.
Huna A, Salmina K, Erenpreisa J, Vazquez-Martin A, Krigerts J, Inashkina I, et al. Role of stress-activated OCT4A in the cell fate decisions of embryonal carcinoma cells treated with etoposide. Cell Cycle. 2015; 14 (18):2969-2984. DOI: 10.1080/15384101.2015.1056948 - 47.
Lee J, Go Y, Kang I, Han YM, Kim J. Oct-4 controls cell-cycle progression of embryonic stem cells. The Biochemical Journal. 2010; 426 (2):171-181. DOI: 10.1042/BJ20091439 - 48.
Boyer LA, Lee TI, Cole MF, Johnstone SE, Levine SS, Zucker JP, et al. Core transcriptional regulatory circuitry in human embryonic stem cells. Cell. 2005; 122 (6):947-956. DOI: 10.1016/j.cell.2005.08.020 - 49.
Lin T, Chao C, Saito S, Mazur SJ, Murphy ME, Appella E, et al. p53 induces differentiation of mouse embryonic stem cells by suppressing Nanog expression. Nature Cell Biology. 2005; 7 (2):165-171. DOI: 10.1038/ncb1211 - 50.
Kalmar T, Lim C, Hayward P, Muñoz-Descalzo S, Nichols J, Garcia-Ojalvo J, et al. Regulated fluctuations in nanog expression mediate cell fate decisions in embryonic stem cells. Goodell MA, editor. PLoS Biology. 2009; 7 (7):e1000149. DOI: 10.1371/journal.pbio.1000149 - 51.
Jones RG, Plas DR, Kubek S, Buzzai M, Mu J, Xu Y, et al. AMP-activated protein kinase induces a p53-dependent metabolic checkpoint. Molecular Cell. 2005; 18 (3):283-293. DOI: 10.1016/j.molcel.2005.03.027 - 52.
Huang S, Eichler G, Bar-Yam Y, Ingber DE. Cell fates as high-dimensional attractor states of a complex gene regulatory network. Physical Reviews Letters. 2005; 94 (12):128701. DOI: 10.1103/PhysRevLett.94.128701 - 53.
Buganim Y, Faddah DA, Jaenisch R. Mechanisms and models of somatic cell reprogramming. Nature Reviews. Genetics.. 2013; 14 (6):427-439. DOI: 10.1038/nrg3473 - 54.
Shin HJ, Kwon HK, Lee JH, Gui X, Achek A, Kim JH, et al. Doxorubicin-induced necrosis is mediated by poly-(ADP-ribose) polymerase 1 (PARP1) but is independent of p53. Scientific Reports. 2015; 5 :15798. DOI: 10.1038/srep15798 - 55.
De Cecco M, Criscione SW, Peckham EJ, Hillenmeyer S, Hamm EA, Manivannan J, et al. Genomes of replicatively senescent cells undergo global epigenetic changes leading to gene silencing and activation of transposable elements. Aging Cell. 2013; 12 (2):247-256. DOI: 10.1111/acel.12047 - 56.
Sturm Á, Ivics Z, Vellai T. The mechanism of ageing: Primary role of transposable elements in genome disintegration. Cellular and Molecular Life Sciences. 2015; 72 (10):1839-1847. DOI: 10.1007/s00018-015-1896-0 - 57.
Salmina K, Huna A, Inashkina I, Belyayev A, Krigerts J, Pastova L, et al. Nucleolar aggresomes mediate release of pericentric heterochromatin and nuclear destruction of genotoxically treated cancer cells. Nucleus. 2017; 8 (2):205-221. DOI: 10.1080/19491034.2017.1279775 - 58.
Vazquez-Martin A, Oliveras-Ferraros C, Cufí S, Martin-Castillo B, Menendez JA. Metformin activates an Ataxia Telangiectasia Mutated (ATM)/Chk2-regulated DNA damage-like response. Cell Cycle. 2011; 10 (9):1499-1501. DOI: 10.4161/cc.10.9.15423 - 59.
Bungard D, Fuerth BJ, Zeng PY, Faubert B, Maas NL, Viollet B, et al. Signaling kinase AMPK activates stress-promoted transcription via histone H2B phosphorylation. Science (80-). 2010; 329 (5996):1201-1205. DOI: 10.1126/science.1191241 - 60.
Law BYK, Gordillo-Martínez F, Qu QY, Zhang N, Xu WS, Cogh PS, et al. Thalidezine, a novel AMPK activator, eliminates apoptosis - resistant cancer cells through energy-mediated autophagic cell death. Oncotarget. 2017 - 61.
Sherman MY, Meng L, Stampfer M, Gabai VL, Yaglom JA. Oncogenes induce senescence with incomplete growth arrest and suppress the DNA damage response in immortalized cells. Aging Cell. 2011; 10 (6):949-961. DOI: 10.1111/j.1474-9726.2011.00736.x - 62.
Erenpreisa J, Salmina K, Huna A, Kosmacek EA, Cragg MS, Ianzini F, et al. Polyploid tumour cells elicit paradiploid progeny through depolyploidizing divisions and regulated autophagic degradation. Cell Biol Int. 2011; 35 (7):687-95. DOI: 10.1042/CBI20100762 - 63.
Erenpreisa J, Ivanov A, Wheatley SP, Kosmacek EA, Ianzini F, Anisimov AP, et al. Endopolyploidy in irradiated p53-deficient tumour cell lines: Persistence of cell division activity in giant cells expressing Aurora-B kinase. Cell Biology International. 2008; 32 (9):1044-1056. DOI: 10.1016/j.cellbi.2008.06.003 - 64.
Unruhe B, Schroder E, Wunsch D, Knauer SK. An old flame never dies: Survivin in cancer and cellular senescence. Gerontology. 2015; 62 (2):173-181. DOI: 10.1159/000432398 - 65.
Vazquez-Martin A, Oliveras-Ferraros C, Menendez JA. The active form of the metabolic sensor AMP-activated protein kinase α (AMPKα) directly binds the mitotic apparatus and travels from centrosomes to the spindle midzone during mitosis and cytokinesis. Cell Cycle. 2009; 8 (15):2385-2398. DOI: 10.4161/cc.8.15.9082 - 66.
Haaf T, Raderschall E, Reddy G, Ward DC, Radding CM, Golub EI. Sequestration of mammalian Rad51-recombination protein into micronuclei. The Journal of Cell Biology. 1999; 144 (1):11-20 - 67.
Rello-Varona S, Lissa D, Shen S, Niso-Santano M, Senovilla L, Mariño G, et al. Autophagic removal of micronuclei. Cell Cycle. 2012; 11 (1):170-176. DOI: 10.4161/cc.11.1.18564 - 68.
Erenpreisa J, Huna A, Salmina K, Jackson TR, Cragg MS. Macroautophagy-aided elimination of chromatin: Sorting of waste, sorting of fate? Autophagy. 2012; 8 (12):1877-1881 - 69.
Erenpreisa JA, Cragg MS, Fringes B, Sharakhov I, Illidge TM. Release of mitotic descendants by giant cells from irradiated Burkitt’s lymphoma cell line. Cell Biology International. 2000; 24 (9):635-648. DOI: 10.1006/cbir.2000.0558 - 70.
Erenpreisa J, Cragg MS. Cancer: A matter of life cycle? Cell Biology International. 2007; 31 (12):1507-1510. DOI: 10.1016/j.cellbi.2007.08.013 - 71.
Erenpreisa J, Cragg MS. Life-cycle features of tumour cells. In: Pontarotti P, editor. Evolutionary Biology from Concept to Application. Berlin, Heidelberg: Springer Berlin Heidelberg; 2008. pp. 61-71. DOI: 10.1007/978-3-540-78993-2_4 - 72.
Vazquez-Martin A, Anatskaya OV, Giuliani A, Erenpreisa J, Huang S, Salmina K, et al. Somatic polyploidy is associated with the upregulation of c-MYC interacting genes and EMT-like signature. Oncotarget. 2016; 7 (46):75235-75260. DOI: 10.18632/oncotarget.12118 - 73.
Kastan MB. Wild-type p53: Tumors can’t stand it. Cell. 2007; 128 (5):837-840. DOI: 10.1016/j.cell.2007.02.022