Actinomycin D and nutlin-3a synergistically promote phosphorylation of p53 on serine 46 in cancer cell lines of different origin

Zajkowicz, Artur; Gdowicz-Kłosok, Agnieszka; Krześniak, Małgorzata; Ścieglińska, Dorota; Rusin, Marek

doi:10.1016/j.cellsig.2015.05.005

Cited by 28 publications

(36 citation statements)

References 40 publications

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“…Interleukin-18 promotes the release of IFN-γ by NK-cells and T-cells [6]. Based on our previously reported observations [1,2] and recent work by other investigators [5,7], we hypothesized that activation of p53 by A + N co-treatment induces pyroptosis of A549 cells. We started this study with testing of this hypothesis.…”

Section: Introductionmentioning

confidence: 88%

“…Actinomycin D and nutlin-3a (A + N) synergistically activate the p53 pathway in various cell lines [1,2]. Actinomycin D is an anticancer drug, which at low concentration inhibits RNA polymerase I (RNA Pol I).…”

Section: Introductionmentioning

confidence: 99%

“…The phosphorylation of Ser46 is difficult to observe in the presence of actinomycin D and is undetectable in the presence of nutlin-3a. However, when both substances are applied together, the status of phospho-Ser46 p53 reaches very high levels [1,2]. The phosphorylation of Ser46 is considered a marker of activated p53, which efficiently stimulates the expression of proapoptotic genes [4].…”

Section: Introductionmentioning

confidence: 99%

“…CPT induces death of A549 cells via characteristic of apoptosis mechanisms including morphology, sub-G1 DNA content and activation of caspase 3. Alternatively, cell death induced by A + N treatment morphologically resembles necrosis, showing characteristics such as the swelling and bursting ("cell ballooning") of the cytoplasm without the extensive cell blebbing that is characteristic of apoptosis [1]. There are several forms of regulated cell death (RCD) including apoptosis, which is characterized by apoptotic morphology.…”

Section: Introductionmentioning

confidence: 99%

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Synergistic activation of p53 by actinomycin D and nutlin-3a is associated with the upregulation of crucial regulators and effectors of innate immunity

Krześniak

Zajkowicz

Gdowicz-Kłosok

et al. 2020

Cellular Signalling

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A B S T R A C TActinomycin D and nutlin-3a (A + N) activate p53, partly through induction of phosphorylation on Ser392. The death of A549 cells induced by A + N morphologically resembles inflammation-inducing pyroptosis -cell destruction triggered by activated caspase-1. The treatment with A + N (or camptothecin) strongly upregulated caspase-1 and its two activators: IFI16 and NLRP1, however, caspase-1 activation was not detected. A549 cells may have been primed for pyroptosis, with the absence of a crucial trigger. The investigation of additional innate immunity elements revealed that A + N (or camptothecin) stimulated the expression of NLRX1, STING (stimulator of interferon genes) and two antiviral proteins, IFIT1 and IFIT3. IFI16 and caspase-1 are coded by p53regulated genes which led us to investigate regulation of NLRP1, NLRX1, STING, IFIT1 and IFIT3 in p53-dependent mode. The upregulation of NLRP1, NLRX1 and STING was attenuated in p53 knockdown cells. The upsurge of the examined genes, and activation of p53, was inhibited by C16, an inhibitor of PKR kinase. PKR was tested due to its ability to phosphorylate p53 on Ser392. Surprisingly, C16 was active even in PKR knockdown cells. The ability of C16 to prevent activation of p53 and expression of innate immunity genes may be the source of its strong anti-inflammatory action. Moreover, cells exposed to A + N can influence neighboring cells in paracrine fashion, for instance, they shed ectodomain of COL17A1 protein and induce, in p53-dependent mode, the expression of gene for interleukin-7. Further, the activation of p53 also spurred the expression of SOCS1, an inhibitor of interferon triggered STAT1-dependent signaling. We conclude that, stimulation of p53 primes cells for the production of interferons (through upregulation of STING), and may activate negative-feedback within this signaling system by enhancing the production of SOCS1.

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Section: Introductionmentioning

confidence: 88%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Synergistic activation of p53 by actinomycin D and nutlin-3a is associated with the upregulation of crucial regulators and effectors of innate immunity

Krześniak

Zajkowicz

Gdowicz-Kłosok

et al. 2020

Cellular Signalling

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“…Does p53 phosphorylation contribute to any tumor suppressive role? Several studies have shown that p53 phosphorylation (eg, Ser15, 20, 37, 46) induces apoptosis through multiple effectors, such as inositol pyrophosphates, selenocysteine, nutlin‐3a, and palmdelphin in cancer cells . Moreover, there has been considerable effort to understand the mechanism of p53 regulation by post‐translational modification using genetically engineered mouse models .…”

Section: P53 Phosphorylation In Tumor Suppressive Rolesmentioning

confidence: 99%

Tumor suppressive role for kinases phosphorylating p53 in DNA damage‐induced apoptosis

2018

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Tumor suppressor p53 plays an important role in cancer prevention. Under normal conditions, p53 is maintained at a low level. However, in response to various cellular stresses, p53 is stabilized and activated, which, in turn, initiates DNA repair, cell‐cycle arrest, senescence and apoptosis. Post‐translational modifications of p53 including phosphorylation, ubiquitination, and acetylation at multiple sites are important to regulate its activation and subsequent transcriptional gene expression. Particularly, phosphorylation of p53 plays a critical role in modulating its activation to induce apoptosis in cancer cells. In this context, previous studies show that several serine/threonine kinases regulate p53 phosphorylation and downstream gene expression. The molecular basis by which p53 and its kinases induce apoptosis for cancer prevention has been extensively studied. However, the relationship between p53 phosphorylation and its kinases and how the activity of kinases is controlled are still largely unclear; hence, they need to be investigated. In this review, we discuss various roles for p53 phosphorylation and its responsible kinases to induce apoptosis and a new therapeutic approach in a broad range of cancers.

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The stress sensor GCN2 differentially controls ribosome biogenesis in colon cancer according to the nutritional context

et al. 2023

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Nutrient availability is a key determinant of tumor cell behavior. While nutrient‐rich conditions favor proliferation and tumor growth, scarcity, and particularly glutamine starvation, promotes cell dedifferentiation and chemoresistance. Here, linking ribosome biogenesis plasticity with tumor cell fate, we uncover that the amino acid sensor general control non‐derepressible 2 (GCN2; also known as eIF‐2‐alpha kinase 4) represses the expression of the precursor of ribosomal RNA (rRNA), 47S, under metabolic stress. We show that blockade of GCN2 triggers cell death by an irremediable nucleolar stress and subsequent TP53‐mediated apoptosis in patient‐derived models of colon adenocarcinoma (COAD). In nutrient‐rich conditions, a cell‐autonomous GCN2 activity supports cell proliferation by stimulating 47S rRNA transcription, independently of the canonical integrated stress response (ISR) axis. Impairment of GCN2 activity prevents nuclear translocation of methionyl‐tRNA synthetase (MetRS), resulting in nucleolar stress, mTORC1 inhibition and, ultimately, autophagy induction. Inhibition of the GCN2–MetRS axis drastically improves the cytotoxicity of RNA polymerase I (RNA pol I) inhibitors, including the first‐line chemotherapy oxaliplatin, on patient‐derived COAD tumoroids. Our data thus reveal that GCN2 differentially controls ribosome biogenesis according to the nutritional context. Furthermore, pharmacological co‐inhibition of the two GCN2 branches and RNA pol I activity may represent a valuable strategy for elimination of proliferative and metabolically‐stressed COAD cells.

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Actinomycin D and nutlin-3a synergistically promote phosphorylation of p53 on serine 46 in cancer cell lines of different origin

Cited by 28 publications

References 40 publications

Synergistic activation of p53 by actinomycin D and nutlin-3a is associated with the upregulation of crucial regulators and effectors of innate immunity

Synergistic activation of p53 by actinomycin D and nutlin-3a is associated with the upregulation of crucial regulators and effectors of innate immunity

Tumor suppressive role for kinases phosphorylating p53 in DNA damage‐induced apoptosis

The stress sensor GCN2 differentially controls ribosome biogenesis in colon cancer according to the nutritional context

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