Senescence and apoptosis: dueling or complementary cell fates?

Childs, Bennett G.; Baker, Darren J.; Kirkland, James L.; Campisi, Judith; Deursen, Jan M. van

doi:10.15252/embr.201439245

Cited by 673 publications

(619 citation statements)

References 143 publications

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“…Of note, senescence can be an alternative route to curb tumor growth where cells get resistance to apoptosis. Generally, apoptosis is a programmed cell death, but an apoptotic cell does not communicate with the surrounding cells, whereas, in contrast to apoptosis, a senescent cell can activate a paracrine signaling within the tumor contributing more benefits than apoptosis (Childs et al 2014;Hoare and Narita 2013). This report suggests that cristacarpin could be considered as a potential lead for senescence induction in cancer cells.…”

Section: Discussionmentioning

confidence: 84%

Cristacarpin promotes ER stress-mediated ROS generation leading to premature senescence by activation of p21waf-1

Chakraborty

Rasool

Kumar

et al. 2016

AGE

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Stress-induced premature senescence (SIPS) is quite similar to replicative senescence that is committed by cells exposed to various stress conditions viz. ultraviolet radiation (DNA damage), hydrogen peroxide (oxidative stress), chemotherapeutic agents (cytotoxic threat), etc. Here, we report that cristacarpin, a natural product obtained from the stem bark of Erythrina suberosa, promotes endoplasmic reticulum (ER) stress, leading to sub-lethal reactive oxygen species (ROS) generation and which eventually terminates by triggering senescence in pancreatic and breast cancer cells through blocking the cell cycle in the G1 phase. The majority of cristacarpin-treated cells responded to conventional SA-β-gal stains; showed characteristic p21 waf1 upregulation along with enlarged and flattened morphology; and increased volume, granularity, and formation of heterochromatin foci-all of these features are the hallmarks of senescence. Inhibition of ROS generation by N-acetyl-L-cysteine (NAC) significantly reduced the expression of p21 waf1 , confirming that the modulation in p21 waf1 by anti-proliferative cristacarpin was ROS dependent. Further, the elevation in p21 waf1 expression in PANC-1 and MCF-7 cells was consistent with the decrease in the expression of Cdk-2 and cyclinD1. Here, we provide evidence that cristacarpin promotes senescence in a p53-independent manner. Moreover, cristacarpin treatment induced p38MAPK, indicating the ROS-dependent activation of the MAP kinase pathway, and thus abrogates the tumor growth in mouse allograft tumor model.

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Section: Discussionmentioning

confidence: 84%

Cristacarpin promotes ER stress-mediated ROS generation leading to premature senescence by activation of p21waf-1

Chakraborty

Rasool

Kumar

et al. 2016

AGE

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“…Resistance to apoptosis and oxidative stress is a hallmark of SCs (Childs, Baker, Kirkland, Campisi & Van Deursen, 2014; Childs et al., 2017) that can be exploited to develop senolytic agents that selectively kill SCs, assuming that the molecules that mediate the resistance can be identified. Indeed, we and others have recently discovered that the upregulation of the antiapoptotic Bcl‐2 family proteins is primarily responsible for the resistance of SCs to apoptosis, and Bcl‐2/xl/w inhibitors such as ABT‐263 are potent senolytic agents (Chang et al., 2016; Yosef et al., 2016; Zhu et al., 2016).…”

Section: Discussionmentioning

confidence: 99%

Oxidation resistance 1 is a novel senolytic target

et al. 2018

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SummaryThe selective depletion of senescent cells (SCs) by small molecules, termed senolytic agents, is a promising therapeutic approach for treating age‐related diseases and chemotherapy‐ and radiotherapy‐induced side effects. Piperlongumine (PL) was recently identified as a novel senolytic agent. However, its mechanism of action and molecular targets in SCs was unknown and thus was investigated. Specifically, we used a PL‐based chemical probe to pull‐down PL‐binding proteins from live cells and then mass spectrometry‐based proteomic analysis to identify potential molecular targets of PL in SCs. One prominent target was oxidation resistance 1 (OXR1), an important antioxidant protein that regulates the expression of a variety of antioxidant enzymes. We found that OXR1 was upregulated in senescent human WI38 fibroblasts. PL bound to OXR1 directly and induced its degradation through the ubiquitin‐proteasome system in an SC‐specific manner. The knockdown of OXR1 expression by RNA interference significantly increased the production of reactive oxygen species in SCs in conjunction with the downregulation of antioxidant enzymes such as heme oxygenase 1, glutathione peroxidase 2, and catalase, but these effects were much less significant when OXR1 was knocked down in non‐SCs. More importantly, knocking down OXR1 selectively induced apoptosis in SCs and sensitized the cells to oxidative stress caused by hydrogen peroxide. These findings provide new insights into the mechanism by which SCs are highly resistant to oxidative stress and suggest that OXR1 is a novel senolytic target that can be further exploited for the development of new senolytic agents.

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“…Actually, senescent cells might maintain an apparent homeostasis by eliminating oversynthesized factors such as those observed in the SASP. SASP has been shown to contribute to the pro-tumorigenic effect of senescence, 41,42 including in MM. 16 Therefore, preventing SASP in MM might lead to a decreased tumorigenesis.…”

Section: Discussionmentioning

confidence: 99%

HIF-1α and rapamycin act as gerosuppressant in multiple myeloma cells upon genotoxic stress

et al. 2016

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Multiple myeloma (MM) is still an incurable hematological malignancy. Despite recent progress due to new anti-myeloma agents, the pathology is characterized by a high frequency of de novo or acquired resistance. Delineating the mechanisms of MM resistance is essential for therapeutic advances. We previously showed that long-term genotoxic stress induces the establishment of a senescence-associated secretory phenotype, a pro-inflammatory response that favors the emergence of cells with cancer stem-like properties. Here, we studied the short-term response of MM cells following treatment with various DNA damaging agents such as the energetic C-ion irradiation. MM cells are highly resistant to all treatments and do not enter apoptosis after they arrest cycling at the G2 phase. Although the DNA damage response pathway was activated, DNA breaks remained chronically in damaged MM cells. We found, using a transcriptomic approach that RAD50, a major DNA repair gene was downregulated early after genotoxic stress. In two gerosuppression situations: induction of hypoxia and inhibition of the mammalian target of rapamycin (mTOR) pathway, we observed, after the treatment with a DNA damaging agent, a normalization of RAD50 expression concomitant with the absence of cell cycle arrest. We propose that combining inhibitors of mTOR with genotoxic agents could avoid MM cells to senesce and secrete proinflammatory factors responsible for cancer stem-like cell emergence and, in turn, relapse of MM patients.

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Senescence and apoptosis: dueling or complementary cell fates?

Cited by 673 publications

References 143 publications

Cristacarpin promotes ER stress-mediated ROS generation leading to premature senescence by activation of p21waf-1

Cristacarpin promotes ER stress-mediated ROS generation leading to premature senescence by activation of p21waf-1

Oxidation resistance 1 is a novel senolytic target

HIF-1α and rapamycin act as gerosuppressant in multiple myeloma cells upon genotoxic stress

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