Apoptosis-resistance of senescent cells is an intrinsic barrier for senolysis induced by cardiac glycosides

Deryabin, Pavel; Shatrova, A. N.; Marakhova, I I; Nikolsky, Nikolay; Borodkina, Aleksandra

doi:10.1101/2020.12.18.423449

Cited by 3 publications

(3 citation statements)

References 66 publications

(29 reference statements)

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“…Cardiac glycosides do induce apoptotic death in human embryonic stem cells (hESCs) but not in hESCderived mesenchymal stem cells and human bone marrow mesenchymal stem cells (hBMMSCs) 66 . As reported recently and also shown in our study, cardiac glycosides do not induce apoptosis in both hMESCs and their senescent partners 105 . Obviously, the high resistance of hMESCs to cardiac glycosides is provided by a highly expressed anti-apoptotic program in these cells 32,64,65,106,107 .…”

Section: Discussionsupporting

confidence: 90%

Monovalent Ions and Stress-Induced Senescence in Human Mesenchymal Endometrial Stem Cells

Shatrova

Пуговкина

Домнина

et al. 2021

Preprint

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Monovalent ions are involved in growth, proliferation, differentiation of cells as well as in their death. This work concerns the ion homeostasis during senescence induction in human mesenchymal endometrium stem cells (hMESC): hMESCs subjected to oxidative stress (pulse H2O2 treatment) enter the premature senescence accompanied by persistent DNA damage, irreversible cell cycle arrest, cell hypertrophy, lipofuscin accumulation, enhanced β-galactosidase activity. Using flame photometry to estimate K+, Na+ content and Rb+ (K+) fluxes we found that during the senescence development in stress-induced hMESCs, Na+/K+pump-mediated K+ fluxes are enhanced due to the increased Na+ content in senescent cells, while ouabain-resistant K+ fluxes remain unchanged. Senescence progression is accompanied by a peculiar decrease in the K+ content in cells from 800-900 µmol/g to 500-600 µmol/g. Since cardiac glycosides are offered as selective agents for eliminating senescent cells, we investigated the effect of ouabain on ion homeostasis and viability of hMESCs and found that in both proliferating and senescent hMESCs, ouabain (1 nM-1 µM, 24-48 h) inhibited pump-mediated K+ transport (ID50 5x10-8 M), decreased cell K+/Na+ ratio to 0,1-0,2, however did not induce apoptosis. Comparison of the effect of ouabain on hMESCs with the literature data on the selective cytotoxic effect of cardiac glycosides on senescent or cancer cells suggests the ion pump blockade and intracellular K+ depletion should be synergized with target apoptotic signal to induce the cell death.

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Section: Discussionsupporting

confidence: 90%

Monovalent Ions and Stress-Induced Senescence in Human Mesenchymal Endometrial Stem Cells

Shatrova

Пуговкина

Домнина

et al. 2021

Preprint

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“…The correct response of ESCs to the increasing levels of steroid hormones during the second phase of the menstrual cycle resulting in decidual transformation of endometrial tissue marks WOI (Deryabin et al, 2020). During this limited time period endometrium becomes receptive and enables further implantation.…”

Section: Resultsmentioning

confidence: 99%

Senescence of stromal cells contributes to endometrium dysfunction and embryo implantation failure

Deryabin

Ivanova

Borodkina

2021

Preprint

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Successful implantation requires two-sided interaction between genetically normal embryo and properly prepared endometrium. At the cellular level the latter means hormone-regulated differentiation of endometrial stromal cells (ESCs) into decidual ones that create appropriate microenvironment for invading embryo. Impaired decidualization is proved to mediate implantation failures. Here we elicited ESCs’ senescence as the cause for disturbed decidualization of endometrial stroma and impaired blastocyst implantation. Ability to decidualize and to accept modeled blastocysts inversely correlated with senescence in patients’ ESCs lines. Reduced hormonal responsiveness of senescent ESCs led to inappropriate decidualization dynamics resulting in altered receptivity, disturbed ligand-receptor interaction with trophoblasts and modified architecture of extracellular matrix what hindered blastocysts’ invasion. Furthermore, senescent ESCs caused ‘bystander’ quenching of decidual reaction in adjacent cells reinforcing dysfunction of stromal compartment. Implementation of senomorphics reducing senescence phenotype diminished adverse effects of senescent ESCs on decidualization and implantation using both in vitro models and patients’ lines, what suggests a promising strategy to increase in vitro fertilization efficacy.

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“…While low doses of cardioglycosides induced the selective senolysis of BRAF-V600E-induced senescent fibroblasts through signal transduction and autophagy inhibition [34], their action in other senescence models was rather attributed to disturbance of membrane potential [33,35]. Interestingly, they proved inefficient in senescent human mesenchymal stem cells that have upregulated processes for potassium import but could nevertheless be primed for senolysis through the inhibition of anti-apoptotic MCL-1 [124]. On the other hand, the authors noted that etoposide-induced senescent A549 cells exhibited a decreased capacity to restore intracellular potassium levels, the drop of which is an early event in apoptosis, and as such made them less resilient in the face of stress, contradicting the notion of senescence-associated apoptosis resistance.…”

Section: Class III Senolytics: Further Disturbing Cellular Homeostati...mentioning

confidence: 99%

From the divergence of senescent cell fates to mechanisms and selectivity of senolytic drugs

2022

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Senescence is a cellular stress response that involves prolonged cell survival, a quasi-irreversible proliferative arrest and a modification of the transcriptome that sometimes includes inflammatory gene expression. Senescent cells are resistant to apoptosis, and if not eliminated by the immune system they may accumulate and lead to chronic inflammation and tissue dysfunction. Senolytics are drugs that selectively induce cell death in senescent cells, but not in proliferative or quiescent cells, and they have proved a viable therapeutic approach in multiple mouse models of pathologies in which senescence is implicated. As the catalogue of senolytic compounds is expanding, novel survival strategies of senescent cells are uncovered, and variations in sensitivity to senolysis between different types of senescent cells emerge. We propose herein a mechanistic classification of senolytic drugs, based on the level at which they target senescent cells: directly disrupting BH3 protein networks that are reorganized upon senescence induction; downregulating survival-associated pathways essential to senescent cells; or modulating homeostatic processes whose regulation is challenged in senescence. With this approach, we highlight the important diversity of senescent cells in terms of physiology and pathways of apoptosis suppression, and we describe possible avenues for the development of more selective senolytics.

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Apoptosis-resistance of senescent cells is an intrinsic barrier for senolysis induced by cardiac glycosides

Cited by 3 publications

References 66 publications

Monovalent Ions and Stress-Induced Senescence in Human Mesenchymal Endometrial Stem Cells

Monovalent Ions and Stress-Induced Senescence in Human Mesenchymal Endometrial Stem Cells

Senescence of stromal cells contributes to endometrium dysfunction and embryo implantation failure

From the divergence of senescent cell fates to mechanisms and selectivity of senolytic drugs

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