The DNA-damage response and nuclear events as regulators of nonapoptotic forms of cell death

Prokhorova, Evgeniia; Egorshina, Aleksandra Yu; Zhivotovsky, Boris; Kopeina, Gelina S.

doi:10.1038/s41388-019-0980-6

Cited by 54 publications

(48 citation statements)

References 165 publications

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“…Cell cycle checkpoints function to protect cells by delaying the progression of the cell cycle until damaged DNA is repaired (31). For cells with irreparable DNA damage, the cell death pathway, primarily intrinsic caspase-dependent apoptosis, is activated (22). In the present study, to reasonably compare our data with previous studies, cells were cultured for 48 h following treatment (8,13,14).…”

Section: Discussionmentioning

confidence: 75%

“…Previous studies have attributed the anti-cancer effects of 125 I seed radiation to DNA damage, G2/M cell cycle arrest and apoptosis (8,14,37,38). DNA damage can be induced directly by radiation or indirectly by radiation-induced ROS (22). Cell cycle checkpoints function to protect cells by delaying the progression of the cell cycle until damaged DNA is repaired (31).…”

Section: Discussionmentioning

confidence: 99%

“…Paraptosis, or paraptosis-like cell death, is characterized by cytoplasmic vacuolation resulting from mitochondria and/or endoplasmic reticulum (ER) swelling, and it lacks typical apoptotic morphological characteristics, including chromatin condensation, nuclear fragmentation and apoptotic body formation (21). Paraptosis differs from necrosis in that, paraptosis does not result in early plasma membrane rupture and the release of cellular contents (21,22). Recent studies have shown that paraptosis-associated cell death is an important anti-cancer mechanism of various natural products, and is a novel area of interest in cancer research (23)(24)(25)(26).…”

Section: Iodine-125 Seed Radiation Induces Ros-mediated Apoptosis Aumentioning

confidence: 99%

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Iodine‑125 seed radiation induces ROS‑mediated apoptosis, autophagy and paraptosis in human esophageal squamous cell carcinoma cells

Wang

Zeng

et al. 2020

Oncol Rep

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Iodine-125 (125 I) seed brachytherapy has been proven to be a safe and effective treatment for advanced esophageal cancer; however, the mechanisms underlying its actions are not completely understood. In the present study, the anti-cancer mechanisms of 125 I seed radiation in human esophageal squamous cell carcinoma (ESCC) cells (Eca-109 and KYSE-150) were determined, with a particular focus on the mode of cell death. The results showed that 125 I seed radiation significantly inhibited cell proliferation, and induced DNA damage and G2/M cell cycle arrest in both ESCC cell lines. 125 I seed radiation induced cell death through both apoptosis and paraptosis. Eca-109 cells were primarily killed by inducing caspase-dependent apoptosis, with 6 Gy radiation resulting in the largest response. KYSE-150 cells were primarily killed by inducing paraptosis, which is characterized by extensive cytoplasmic vacuolation. 125 I seed radiation induced autophagic flux in both ESCC cell lines, and autophagy inhibition by 3-methyladenine enhanced radiosensitivity. Furthermore 125 I seed radiation induced increased production of reactive oxygen species (ROS) in both ESCC cell lines. Treatment with an ROS scavenger significantly attenuated the effects of 125 I seed radiation on endoplasmic reticulum stress, autophagy, apoptosis, paraptotic vacuoles and reduced cell viability. In vivo experiments showed that 125 I seed brachytherapy induced ROS generation, initiated cell apoptosis and potential paraptosis, and inhibited cell proliferation and tumor growth. In summary, the results demonstrate that in ESCC cells, 125 I seed radiation induces cell death through both apoptosis and paraptosis; and at the same time initiates protective autophagy. Additionally, 125 I seed radiation-induced apoptosis, paraptosis and autophagy was considerably mediated by ROS.

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Section: Discussionmentioning

confidence: 75%

Section: Discussionmentioning

confidence: 99%

Section: Iodine-125 Seed Radiation Induces Ros-mediated Apoptosis Aumentioning

confidence: 99%

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Iodine‑125 seed radiation induces ROS‑mediated apoptosis, autophagy and paraptosis in human esophageal squamous cell carcinoma cells

Wang

Zeng

et al. 2020

Oncol Rep

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“…In addition, caspase-2 has been reported to be indispensable for the proper cell proliferation, genomic stability, response to ER and oxidative stress 8 . Moreover, this protein negatively regulates necroptosis and performs a number of non-apoptotic functions 9,10 . Caspase-2, as one of the initiator caspases, has a long prodomain which contains a caspase recruitment domain (CARD).…”

Section: Introductionmentioning

confidence: 99%

Requirement for Serine-384 in Caspase-2 processing and activity

et al. 2020

Self Cite

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Caspase-2 is a unique and conservative cysteine protease which plays an important role in several cellular processes including apoptotic cell death. Although the molecular mechanisms of its activation remain largely unclear, a major role belongs to the architecture of the caspase-2 active center. We demonstrate that the substitution of the putative phosphorylation site of caspase-2, Serine-384 to Alanine, blocks caspase-2 processing and decreases its enzymatic activity. Strikingly, in silico analysis using molecular dynamics simulations has shown that Serine-384 is crucially involved in interactions within the caspase-2 active center. It stabilizes Arginine-378, which forms a crucial hydrogen bond with the aspartate residue of a substrate. Hence, Serine-384 is essential for supporting a proper architecture of the active center of caspase-2. Moreover, molecular modeling strongly proved steric inaccessibility of Ser-384 to be phosphorylated. Importantly, a multiple alignment has demonstrated that both Serine-384 and Arg-378 residues are highly conservative across all members of caspase family, which allows us to suggest that this diade is indispensable for caspase processing and activity. Spontaneous mutations in this diade might influence oncosuppressive function of caspases, in particular of caspase-2. Likewise, the mutation of Ser-384 is associated with the development of lung squamous cell carcinoma and adenocarcinoma. Taken together, we have uncovered a central feature of the caspase-2 activation mechanism which is crucial for the regulation of its signaling network.

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“…Currently, most anticancer drugs function by inducing the apoptosis of cells; however, the dysfunction of apoptosis during cancer cell evolution can cause MDR and result in therapy failure [7] . Importantly, a growing body of literature shows that apoptosis is not the sole anticancer mechanism and that the activation of nonapoptotic cell death is a promising strategy for overcoming MDR [8,9] . Mitotic catastrophe (MC) is a newly identi ed type of anticancer mechanism in cancer treatment and MDR prevention and has received more attention in recent years [10,11] .…”

Section: Introductionmentioning

confidence: 99%

Survivin Suppression Strengthens BZML-induced Mitotic Catastrophe to Overcome Multidrug Resistance by Removing Senescent A549/Taxol Cells

Bai¹,

Zhou²,

Ye³

et al. 2020

Preprint

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Background: Mitotic catastrophe (MC) of cancer cells induced by BZML, a novel colchicine-binding site inhibitor, exerts a significant advantage in overcoming multidrug resistance (MDR) in NSCLC. However, the long cellular death process resulting from MC is not beneficial for anticancer treatment. Here, we study the mechanisms underlying MC occurrence and development to promote the development of anticancer therapies based on drug-induced MC.Methods: Cellular senescence was confirmed by morphological features, SA-β-Gal and C12FDG staining. Cell cycle analysis and Hoechst 33342 staining were used to detect MC. Relevant signal transduction pathways and protein location were detected by qRT-PCR, westren blot and immunofluorescence. The half-life of proteins was evaluated using the protein synthesis inhibitor cycloheximide. Flow cytometry, MTT assay, crystal violet staining, Hoechst 33342 staining and cell division detection were performed to determine the effects of BZML and/or YM155 on cell fate. Results: We found that BZML induced p53-dependent cellular senescence in A549/Taxol cells, but not in A549, H1299 and MDA-MB-231 cells. Interestingly, BZML-induced senescence was a secondary effect of MC. In addition, the destruction of the protein-degradation system induced by BZML contributed not only to an increase in p53 protein but also to the accumulation of survivin in the nucleus of A549/Taxol cells. However, in A549 cells, the overexpression of survivin had no effect on apoptosis resistance against BZML and failed to promote BZML-induced MC. The inhibition of survivin did not prevent MC occurrence. Unexpectedly, targeting survivin with YM155 accelerated the death of the MC cells by eliminating senescent cells and strengthening the efficiency of BZML in overcoming the MDR of A549/Taxol cells.Conclusions: Our data suggest that nuclear accumulation of survivin can delay cellular death during MC by promoting the survival of senescent BZML-treated A549/Taxol cells. Further, depending on the dose sequence, combination therapy with YM155 to inhibit survivin might be a new strategy for potentiating BZML-induced MC to overcome MDR during cancer treatment.

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The DNA-damage response and nuclear events as regulators of nonapoptotic forms of cell death

Cited by 54 publications

References 165 publications

Iodine‑125 seed radiation induces ROS‑mediated apoptosis, autophagy and paraptosis in human esophageal squamous cell carcinoma cells

Iodine‑125 seed radiation induces ROS‑mediated apoptosis, autophagy and paraptosis in human esophageal squamous cell carcinoma cells

Requirement for Serine-384 in Caspase-2 processing and activity

Survivin Suppression Strengthens BZML-induced Mitotic Catastrophe to Overcome Multidrug Resistance by Removing Senescent A549/Taxol Cells

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