DNA damage causes TP53-dependent coupling of self-renewal and senescence pathways in embryonal carcinoma cells

Jackson, Thomas R.; Salmiņa, Kristīne; Huna, Anda; Inashkina, Inna; Jankevics, Eriks; Riekstiņa, Una; Kalniņa, Zane; Ivanov, Andrey A.; Townsend, Paul A.; Cragg, Mark S.; Ērenpreisa, Jekaterina

doi:10.4161/cc.23285

Cited by 43 publications

(56 citation statements)

References 43 publications

(53 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Markers of accelerated senescence and DNA damage were unexpectedly found to be linked to markers of stemness in senescing IMR-90 fibroblasts [56] and etoposide-or irradiation treated tumour cells arrested in G2-phase [57, 58]. The p21-dependent senescence related to stemness pathways (TGF-β and PI3K) was revealed in normal embryogenesis [79].…”

mentioning

confidence: 99%

“…Interestingly, our recent research on etoposide-treated embryonal carcinoma cells showed that a potential regulator and trigger for this switch is OCT4 (POU5F1), a carrier of life-cycle totipotency [82]; and induced in a TP53-dependent manner alongside p21CIP1. The choice between the two opposite cell fates (reinitiate cell divisions or undergo terminal senescence) in transiently bi-potential cells is undertaken in G2 arrest [57] and this barrier can become adapted to start polyploidy [56]. When the tetraploidy barrier is overcome, the TP53 tumour-suppressing function becomes surpassed [83], likely by methylation of its promoter [84], while mTOR linking to p21-mediated senescence becomes suppressed, thus allowing the reversal of senescence [58].…”

mentioning

confidence: 99%

See 1 more Smart Citation

The “virgin birth”, polyploidy, and the origin of cancer

et al. 2014

Self Cite

View full text Add to dashboard Cite

Recently, it has become clear that the complexity of cancer biology cannot fully be explained by somatic mutation and clonal selection. Meanwhile, data have accumulated on how cancer stem cells or stemloids bestow immortality on tumour cells and how reversible polyploidy is involved. Most recently, single polyploid tumour cells were shown capable of forming spheroids, releasing EMT-like descendents and inducing tumours in vivo. These data refocus attention on the centuries-old embryological theory of cancer. This review attempts to reconcile seemingly conflicting data by viewing cancer as a pre-programmed phylogenetic life-cycle-like process. This cycle is apparently initiated by a meiosis-like process and driven as an alternative to accelerated senescence at the DNA damage checkpoint, followed by an asexual syngamy event and endopolyploid-type embryonal cleavage to provide germ-cell-like (EMT) cells. This cycle is augmented by genotoxic treatments, explaining why chemotherapy is rarely curative and drives resistance. The logical outcome of this viewpoint is that alternative treatments may be more efficacious - either those that suppress the endopolyploidy-associated ‘life cycle’ or, those that cause reversion of embryonal malignant cells into benign counterparts. Targets for these opposing strategies are components of the same molecular pathways and interact with regulators of accelerated senescence.

show abstract

mentioning

confidence: 99%

mentioning

confidence: 99%

The “virgin birth”, polyploidy, and the origin of cancer

et al. 2014

Self Cite

View full text Add to dashboard Cite

show abstract

“…The most surprising fact was that regulators of the opposing processes of senescence (p21CIP1) and self-renewal OCT4A (POU5F1) were highly induced in the same G2-arrested cells (Figures 2C and 4A). This was downstream of activated TP53, as both p21 and partly OCT4A became downregulated after TP53 RNAi silencing ( Figure 2C) [45]. Further study [46] revealed that p53-activated OCT4A down-regulated p21CIP1, moderating its expression and preventing cells from precipitating terminal senescence or apoptosis (Figure 2D), thus providing the opportunity for repair.…”

Section: Ovarian Germline Cells Challenged By Genotoxic Stress Displamentioning

confidence: 99%

“…P53 is activated and simultaneously induces p21CIP1 and OCT4A. OCT4A moderates the expression of p21CIP1 preventing apoptosis or terminal senescence [45,46]. Activated p53 also downregulates the promoter of Nanog gene [49].…”

Section: Transient Bi-potentiality Of Csc For Senescence and Self-renmentioning

confidence: 99%

“…These cells are wt TP53, possessing features of embryonal carcinoma [44]. They were treated with etoposide (ETO), the inhibitor of Topoisomerase II, to induce DSB through the impairment of S-phase [45]. Cells entered massive, prolonged, G2-arrest, acquired lat morphology, and signaled persistent DDR for about 4-5 days in nearly 100% of cell nuclei (positive for γ-H2AX and CHK2 foci) with some cells overcoming the tetraploid barrier (Figure 2A, B).…”

Section: Ovarian Germline Cells Challenged By Genotoxic Stress Displamentioning

confidence: 99%

See 1 more Smart Citation

Accelerated Senescence of Cancer Stem Cells: A Failure to Thrive or a Route to Survival?

Ērenpreisa¹,

Salmiņa²,

Cragg³

2017

Senescence - Physiology or Pathology

Self Cite

View full text Add to dashboard Cite

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 suicient cellular energy remains; generated through autophagy, itself sequestrating p16INK4A in the cytoplasm. As such, autophagic capacity is the botleneck 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 inal 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.

show abstract