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Role of Apoptosis and Cellular Senescence in Cancer and Aging

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (31 May 2023) | Viewed by 21673

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Prof. Dr. Rumiana Tzoneva

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Institute of Biophysics and Biomedical Engineering, Bulgarian Academy of Sciences, 1113 Sofia, Bulgaria
Interests: cell biology; antioxidants; transmembrane signalisation; actin cytoskeleton; anti-tumor therapy; cytotoxicity; apoptosis
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Dear Colleagues,

Apoptosis and cellular senescence are two types of cellular responses to various irreversible dysfunctions caused by cellular damage. Both cellular responses are changed in cancer and aging. While in carcinogenesis, the ability of cells to trigger apoptosis and aging progressively decreases, in aging, the accumulation of senescent cells increases, and the rate of apoptosis also significantly grows. Depending on age, the above model suggests apoptosis and cellular senescence function as the main mechanisms of tumor suppression, providing an effective antitumor strategy in the early and reproductive stages of life, but both become destructive and promote aging later in life. In this regard, understanding the mechanisms that determine the delicate balance between apoptosis and cellular senescence will contribute significantly to the therapeutic use of both processes in developing future strategies to combat cancer and aging and to minimize the side effects of such strategies.

This Special Issue is calling both original articles and reviews providing to the readers of IJMS an elucidation of the understanding about the relationship between apoptosis and cellular senescence and their role in pathological processes as cancer and aging, in order to develop novel research approaches and therapeutic strategies.

Prof. Dr. Rumiana Tzoneva
Guest Editor

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Keywords

cellular senescence
cellular damage
apoptosis
aging

Published Papers (10 papers)

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Editorial

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5 pages, 187 KiB

Open AccessEditorial

Special Issue “Role of Apoptosis and Cellular Senescence in Cancer and Aging”

by Rumiana Tzoneva

Int. J. Mol. Sci. 2024, 25(4), 2103; https://doi.org/10.3390/ijms25042103 - 09 Feb 2024

Viewed by 704

Abstract

The intention of this Special Issue is to elucidate the role of apoptosis and cellular senescence in different pathological processes, such as cancer and aging [...] Full article

(This article belongs to the Special Issue Role of Apoptosis and Cellular Senescence in Cancer and Aging)

Research

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15 pages, 2005 KiB

Open AccessArticle

Cancer History Avoids the Increase of Senescence Markers in Peripheral Cells of Amnestic Mild Cognitive Impaired Patients

by Carol D. SanMartín, Felipe Salech, Daniela Paz Ponce, Jorge Concha-Cerda, Esteban Romero-Hernández, Gianella Liabeuf, Nicole K. Rogers, Paola Murgas, Bárbara Bruna, Jamileth More and María I. Behrens

Int. J. Mol. Sci. 2023, 24(8), 7364; https://doi.org/10.3390/ijms24087364 - 17 Apr 2023

Viewed by 1493

Abstract

Epidemiological studies show that having a history of cancer protects from the development of Alzheimer’s Disease (AD), and vice versa, AD protects from cancer. The mechanism of this mutual protection is unknown. We have reported that the peripheral blood mononuclear cells (PBMC) of amnestic cognitive impairment (aMCI) and Alzheimer’s Disease (AD) patients have increased susceptibility to oxidative cell death compared to control subjects, and from the opposite standpoint a cancer history is associated with increased resistance to oxidative stress cell death in PBMCs, even in those subjects who have cancer history and aMCI (Ca + aMCI). Cellular senescence is a regulator of susceptibility to cell death and has been related to the pathophysiology of AD and cancer. Recently, we showed that cellular senescence markers can be tracked in PBMCs of aMCI patients, so we here investigated whether these senescence markers are dependent on having a history of cancer. Senescence-associated βeta-galactosidase (SA-β-Gal) activity, G0-G1 phase cell-cycle arrest, p16 and p53 were analyzed by flow cytometry; phosphorylated H2A histone family member X (γH2AX) by immunofluorescence; IL-6 and IL-8 mRNA by qPCR; and plasmatic levels by ELISA. Senescence markers that were elevated in PBMCs of aMCI patients, such as SA-β-Gal, Go-G1 arrested cells, IL-6 and IL-8 mRNA expression, and IL-8 plasmatic levels, were decreased in PBMCs of Ca + aMCI patients to levels similar to those of controls or of cancer survivors without cognitive impairment, suggesting that cancer in the past leaves a fingerprint that can be peripherally traceable in PBMC samples. These results support the hypothesis that the senescence process might be involved in the inverse association between cancer and AD. Full article

(This article belongs to the Special Issue Role of Apoptosis and Cellular Senescence in Cancer and Aging)

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19 pages, 5269 KiB

Open AccessArticle

Viscoelastic Liquid Matrix with Faster Bulk Relaxation Time Reinforces the Cell Cycle Arrest Induction of the Breast Cancer Cells via Oxidative Stress

by Mazaya Najmina, Mitsuhiro Ebara, Takahito Ohmura and Koichiro Uto

Int. J. Mol. Sci. 2022, 23(23), 14637; https://doi.org/10.3390/ijms232314637 - 24 Nov 2022

Cited by 4 | Viewed by 2005

Abstract

The reactivating of disseminated dormant breast cancer cells in a soft viscoelastic matrix is mostly correlated with metastasis. Metastasis occurs due to rapid stress relaxation owing to matrix remodeling. Here, we demonstrate the possibility of promoting the permanent cell cycle arrest of breast cancer cells on a viscoelastic liquid substrate. By controlling the molecular weight of the hydrophobic molten polymer, poly(ε-caprolactone-co-D,L-lactide) within 35–63 g/mol, this study highlights that MCF7 cells can sense a 1000 times narrower relaxation time range (80–290 ms) compared to other studies by using a crosslinked hydrogel system. We propose that the rapid bulk relaxation response of the substrate promotes more reactive oxygen species generation in the formed semi-3D multicellular aggregates of breast cancer cells. Our finding sheds light on the potential role of bulk stress relaxation in a viscous-dominant viscoelastic matrix in controlling the cell cycle arrest depth of breast cancer cells. Full article

(This article belongs to the Special Issue Role of Apoptosis and Cellular Senescence in Cancer and Aging)

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17 pages, 2962 KiB

Open AccessArticle

The Effect of Circumscribed Exposure to the Pan-Aurora Kinase Inhibitor VX-680 on Proliferating Euploid Cells

by Xumei Liu, Qiong Shi, Namrta Choudhry, Ting Zhang, Hong Liu, Shenqiu Zhang, Jing Zhang and Dun Yang

Int. J. Mol. Sci. 2022, 23(20), 12104; https://doi.org/10.3390/ijms232012104 - 11 Oct 2022

Cited by 2 | Viewed by 1614

Abstract

Small molecule inhibitors of aurora kinases are currently being investigated in oncology clinical trials. The long-term effects of these inhibitors on proliferating euploid cells have not been adequately studied. We examined the effect of the reversible pan-aurora kinase inhibitor VX-680 on p53-competent human euploid cells. Circumscribed treatment with VX-680 blocked cytokinesis and arrested cells in G1 or a G1-like status. Approximately 70% of proliferatively arrested cells had 4N DNA content and abnormal nuclei. The remaining 30% of cells possessed 2N DNA content and normal nuclei. The proliferative arrest was not due to the activation of the tumor suppressor Rb and was instead associated with rapid induction of the p53–p21 pathway and p16. The induction was particularly evident in cells with nuclear abnormalities but was independent of activation of the DNA damage response. All of these effects were correlated with the potent inhibition of aurora kinase B. After release from VX-680, the cells with normal nuclei robustly resumed proliferation whereas the cells with abnormal nuclei underwent senescence. Irrespective of their nuclear morphology or DNA content, cells pre-treated with VX-680 failed to grow in soft agar or form tumors in mice. Our findings indicate that an intermittent treatment strategy might minimize the on-target side effects of Aurora Kinase B (AURKB) inhibitory therapies. The strategy allows a significant fraction of dividing normal cells to resume proliferation. Full article

(This article belongs to the Special Issue Role of Apoptosis and Cellular Senescence in Cancer and Aging)

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17 pages, 6347 KiB

Open AccessArticle

Oxygen–Glucose Deprivation Promoted Fibroblast Senescence and Collagen Expression via IL11

by Tongtong Song, Yiwen Gu, Wenting Hui, Xiaoyu Yang, Yanqing Liu and Xia Chen

Int. J. Mol. Sci. 2022, 23(20), 12090; https://doi.org/10.3390/ijms232012090 - 11 Oct 2022

Cited by 3 | Viewed by 1745

Abstract

Cell senescence is one of the most important forms of injury induced by cardiovascular and other ischemic diseases. Fibroblasts are important participants in tissue repair after ischemic injury and the main source of IL11 secretion. However, the roles of oxygen–glucose deprivation (OGD) and IL11 in promoting fibroblast senescence and their regulatory mechanisms remain unclear. This study selected the NIH3T3 and L929 fibroblast cell lines as research objects. We found that OGD could induce the expression of p53, P16, p21, and collagen in fibroblasts. In the condition of OGD, when IL11 intervened, fibroblasts’ senescence and collagen expression were changed. Some studies have found that changes in kynurenine (KYN) metabolism are related to aging diseases, and indoleamine 2,3-dioxygenase 1 (IDO1) is a key rate-limiting enzyme in the KYN metabolic pathway. We found that KYN secretion decreased after OGD increased fibroblast senescence, and inhibition of IL11 promoted IDO1 and increased KYN secretion. These results suggest that OGD may promote fibroblast senescence and collagen expression via IL11 inhibition of the IDO1/KYN metabolic pathway. Therefore, the revealed mechanism of OGD-promoted fibroblast senescence could provide an effective theoretical basis for the clinical treatment of aging-related ischemic diseases. Full article

(This article belongs to the Special Issue Role of Apoptosis and Cellular Senescence in Cancer and Aging)

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15 pages, 2617 KiB

Open AccessArticle

Effect of Tauroursodeoxycholic Acid on Inflammation after Ocular Alkali Burn

by Yanqiao Huang, Lixia Lin, Yao Yang, Fang Duan, Miner Yuan, Bingsheng Lou and Xiaofeng Lin

Int. J. Mol. Sci. 2022, 23(19), 11717; https://doi.org/10.3390/ijms231911717 - 03 Oct 2022

Cited by 3 | Viewed by 1716

Abstract

Inflammation is the main cause of corneal and retinal damage in an ocular alkali burn (OAB). The aim of this study was to investigate the effect of tauroursodeoxycholic acid (TUDCA) on ocular inflammation in a mouse model of an OAB. An OAB was induced in C57BL/6j mouse corneas by using 1 M NaOH. TUDCA (400 mg/kg) or PBS was injected intraperitoneally (IP) once a day for 3 days prior to establishing the OAB model. A single injection of Infliximab (6.25 mg/kg) was administered IP immediately after the OAB. The TUDCA suppressed the infiltration of the CD45-positive cells and decreased the mRNA and protein levels of the upregulated TNF-α and IL-1β in the cornea and retina of the OAB. Furthermore, the TUDCA treatment inhibited the retinal glial activation after an OAB. The TUDCA treatment not only ameliorated CNV and promoted corneal re-epithelization but also attenuated the RGC apoptosis and preserved the retinal structure after the OAB. Finally, the TUDCA reduced the expression of the endoplasmic reticulum (ER) stress molecules, IRE1, GRP78 and CHOP, in the retinal tissues of the OAB mice. The present study demonstrated that the TUDCA inhibits ocular inflammation and protects the cornea and retina from injury in an OAB mouse model. These results provide a potential therapeutic intervention for the treatment of an OAB. Full article

(This article belongs to the Special Issue Role of Apoptosis and Cellular Senescence in Cancer and Aging)

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15 pages, 2068 KiB

Open AccessArticle

Senescence Markers in Peripheral Blood Mononuclear Cells in Amnestic Mild Cognitive Impairment and Alzheimer’s Disease

by Felipe Salech, Carol D. SanMartín, Jorge Concha-Cerda, Esteban Romero-Hernández, Daniela P. Ponce, Gianella Liabeuf, Nicole K. Rogers, Paola Murgas, Bárbara Bruna, Jamileth More and María I. Behrens

Int. J. Mol. Sci. 2022, 23(16), 9387; https://doi.org/10.3390/ijms23169387 - 20 Aug 2022

Cited by 9 | Viewed by 2473

Abstract

Recent studies suggest that cellular senescence plays a role in Alzheimer’s Disease (AD) pathogenesis. We hypothesize that cellular senescence markers might be tracked in the peripheral tissues of AD patients. Senescence hallmarks, including altered metabolism, cell-cycle arrest, DNA damage response (DDR) and senescence secretory associated phenotype (SASP), were measured in peripheral blood mononuclear cells (PBMCs) of healthy controls (HC), amnestic mild cognitive impairment (aMCI) and AD patients. Senescence-associated βeta-galactosidase (SA-β-Gal) activity, G0-G1 phase cell-cycle arrest, p16 and p53 were analyzed by flow cytometry, while IL-6 and IL-8 mRNA were analyzed by qPCR, and phosphorylated H2A histone family member X (γH2AX) was analyzed by immunofluorescence. Senescent cells in the brain tissue were determined with lipofuscin staining. An increase in the number of senescent cells was observed in the frontal cortex and hippocampus of advanced AD patients. PBMCs of aMCI patients, but not in AD, showed increased SA-β-Gal compared with HCs. aMCI PBMCs also had increased IL-6 and IL8 mRNA expression and number of cells arrested at G0-G1, which were absent in AD. Instead, AD PBMCs had significantly increased p16 and p53 expression and decreased γH2Ax activity compared with HC. This study reports that several markers of cellular senescence can be measured in PBMCs of aMCI and AD patients. Full article

(This article belongs to the Special Issue Role of Apoptosis and Cellular Senescence in Cancer and Aging)

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Review

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27 pages, 2232 KiB

Open AccessReview

Endothelial Senescence and Its Impact on Angiogenesis in Alzheimer’s Disease

by Irina Georgieva, Jana Tchekalarova, Dimitar Iliev and Rumiana Tzoneva

Int. J. Mol. Sci. 2023, 24(14), 11344; https://doi.org/10.3390/ijms241411344 - 12 Jul 2023

Cited by 2 | Viewed by 1801

Abstract

Endothelial cells are constantly exposed to environmental stress factors that, above a certain threshold, trigger cellular senescence and apoptosis. The altered vascular function affects new vessel formation and endothelial fitness, contributing to the progression of age-related diseases. This narrative review highlights the complex interplay between senescence, oxidative stress, extracellular vesicles, and the extracellular matrix and emphasizes the crucial role of angiogenesis in aging and Alzheimer’s disease. The interaction between the vascular and nervous systems is essential for the development of a healthy brain, especially since neurons are exceptionally dependent on nutrients carried by the blood. Therefore, anomalies in the delicate balance between pro- and antiangiogenic factors and the consequences of disrupted angiogenesis, such as misalignment, vascular leakage and disturbed blood flow, are responsible for neurodegeneration. The implications of altered non-productive angiogenesis in Alzheimer’s disease due to dysregulated Delta-Notch and VEGF signaling are further explored. Additionally, potential therapeutic strategies such as exercise and caloric restriction to modulate angiogenesis and vascular aging and to mitigate the associated debilitating symptoms are discussed. Moreover, both the roles of extracellular vesicles in stress-induced senescence and as an early detection marker for Alzheimer’s disease are considered. The intricate relationship between endothelial senescence and angiogenesis provides valuable insights into the mechanisms underlying angiogenesis-related disorders and opens avenues for future research and therapeutic interventions. Full article

(This article belongs to the Special Issue Role of Apoptosis and Cellular Senescence in Cancer and Aging)

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13 pages, 5526 KiB

Open AccessReview

Nutritional Sensor REDD1 in Cancer and Inflammation: Friend or Foe?

by Ekaterina M. Zhidkova, Evgeniya S. Lylova, Diana D. Grigoreva, Kirill I. Kirsanov, Alena V. Osipova, Evgeny P. Kulikov, Sergey A. Mertsalov, Gennady A. Belitsky, Irina Budunova, Marianna G. Yakubovskaya and Ekaterina A. Lesovaya

Int. J. Mol. Sci. 2022, 23(17), 9686; https://doi.org/10.3390/ijms23179686 - 26 Aug 2022

Cited by 6 | Viewed by 3160

Abstract

Regulated in Development and DNA Damage Response 1 (REDD1)/DNA Damage-Induced Transcript 4 (DDIT4) is an immediate early response gene activated by different stress conditions, including growth factor depletion, hypoxia, DNA damage, and stress hormones, i.e., glucocorticoids. The most known functions of REDD1 are the inhibition of proliferative signaling and the regulation of metabolism via the repression of the central regulator of these processes, the mammalian target of rapamycin (mTOR). The involvement of REDD1 in cell growth, apoptosis, metabolism, and oxidative stress implies its role in various pathological conditions, including cancer and inflammatory diseases. Recently, REDD1 was identified as one of the central genes mechanistically involved in undesirable atrophic effects induced by chronic topical and systemic glucocorticoids widely used for the treatment of blood cancer and inflammatory diseases. In this review, we discuss the role of REDD1 in the regulation of cell signaling and processes in normal and cancer cells, its involvement in the pathogenesis of different diseases, and the approach to safer glucocorticoid receptor (GR)-targeted therapies via a combination of glucocorticoids and REDD1 inhibitors to decrease the adverse atrophogenic effects of these steroids. Full article

(This article belongs to the Special Issue Role of Apoptosis and Cellular Senescence in Cancer and Aging)

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Other

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28 pages, 1939 KiB

Open AccessHypothesis

Revisiting Epithelial Carcinogenesis

by Luis Fernando Méndez-López

Int. J. Mol. Sci. 2022, 23(13), 7437; https://doi.org/10.3390/ijms23137437 - 04 Jul 2022

Cited by 7 | Viewed by 3872

Abstract

The origin of cancer remains one of the most important enigmas in modern biology. This paper presents a hypothesis for the origin of carcinomas in which cellular aging and inflammation enable the recovery of cellular plasticity, which may ultimately result in cancer. The hypothesis describes carcinogenesis as the result of the dedifferentiation undergone by epithelial cells in hyperplasia due to replicative senescence towards a mesenchymal cell state with potentially cancerous behavior. In support of this hypothesis, the molecular, cellular, and histopathological evidence was critically reviewed and reinterpreted when necessary to postulate a plausible generic series of mechanisms for the origin and progression of carcinomas. In addition, the implications of this theoretical framework for the current strategies of cancer treatment are discussed considering recent evidence of the molecular events underlying the epigenetic switches involved in the resistance of breast carcinomas. The hypothesis also proposes an epigenetic landscape for their progression and a potential mechanism for restraining the degree of dedifferentiation and malignant behavior. In addition, the manuscript revisits the gradual degeneration of the nonalcoholic fatty liver disease to propose an integrative generalized mechanistic explanation for the involution and carcinogenesis of tissues associated with aging. The presented hypothesis might serve to understand and structure new findings into a more encompassing view of the genesis of degenerative diseases and may inspire novel approaches for their study and therapy. Full article

(This article belongs to the Special Issue Role of Apoptosis and Cellular Senescence in Cancer and Aging)

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