Radiation-Induced Caspase-8 Mediates p53-Independent Apoptosis in Glioma Cells

Afshar, Golnar; Jelluma, Nannette; Yang, Xiaodong; Basila, Desiree; Arvold, Nils D.; Karlsson, Amelia; Yount, Garret; Dansen, Tobias B.; Koller, Erich; Haas‐Kogan, Daphne A.

doi:10.1158/0008-5472.can-05-1283

Cited by 57 publications

(46 citation statements)

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“…In addition, though the early cell loss that is seen after radiation may occur by apoptosis and mitotic catastrophe, caspase 1-mediated cell death by pyroptosis appears to be an ongoing process after radiation exposure (2). In relation to this observation, links between activation of tumor suppressor p53 and the activation of caspases in cells have been described (29-31). Moreover, it is known that radiation exposure increases p53 expression in cells that undergo radiation-induced apoptosis but p53 can also protect cells from death by acting as a DNA repair enzyme (32).…”

Section: Discussionmentioning

confidence: 96%

Radiation Exposure Induces Inflammasome Pathway Activation in Immune Cells

Stoecklein

Osuka

Ishikawa

et al. 2015

The Journal of Immunology

104

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Radiation exposure induces cell and tissue damage causing local and systemic inflammatory responses. Since the inflammasome pathway is triggered by cell death and danger-associated molecular patterns (DAMPs), we hypothesized that the inflammasome may signal acute and chronic immune responses to radiation. Using a mouse radiation model, we show that radiation induces a dose-dependent increase in inflammasome activation in macrophages, dendritic cells, NK cells, T cells, and B cells as judged by cleaved caspase 1 detection in cells. Time course analysis showed the appearance of cleaved caspase 1 in cells by day 1 and sustained expression until day 7 post-radiation. Also, cells showing inflammasome activation co-expressed the cell-surface apoptosis marker, Annexin V. The role of caspase 1 as a trigger for hematopoietic cell losses after radiation was studied in caspase 1 −/− mice. We found less radiation-induced cell apoptosis and immune cell loss in caspase 1 −/− mice than control mice. Next, we tested whether uric acid might mediate inflammasome activation in cells by treating mice with allopurinol and discovered that allopurinol treatment completely blocked caspase 1 activation in cells. Finally, we demonstrate that radiation-induced caspase 1 activation occurs by a Nod-like receptor family protein 3 (NLRP3) independent mechanism since radiation-exposed Nlrp3 −/− mice showed caspase 1 activation profiles that were indistinguishable from wild-type mice. In summary, our data demonstrate that inflammasome activation occurs in many immune cell types following radiation exposure and that allopurinol prevented radiation-induced inflammasome activation. These results suggest that targeting the inflammasome may help control radiation-induced inflammation.

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Section: Discussionmentioning

confidence: 96%

Radiation Exposure Induces Inflammasome Pathway Activation in Immune Cells

Stoecklein

Osuka

Ishikawa

et al. 2015

The Journal of Immunology

104

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“…Some reports concerning radiation-induced apoptosis, however, have revealed a p53-independent pathway, in which caspase-8 and -3 were activated in HL-60 cells [14] and caspase-8 in glioma cells [12]. Hara et al [13] showed that in glioma U87-W E6 cells, which lost functional p53, radiation-induced apoptosis were associated with formation of ceramide by acid sphingomyelinase and activation of caspase-3.…”

Section: Discussionmentioning

confidence: 99%

“…Bax and Bcl-2) [3], Fas [9,10] and caspases [3]. On the other hand, p53-deficient cell lines, such as HL-60 cells, retain the ability to undergo radiation-induced apoptosis, suggesting that there are p53-independent pathways of apoptosis [8,11,12]. Hara et al [13] have shown that p53-independent induction of apoptosis following ionizing radiation exposure is mediated by sphingomyelinase/ceramide via the stress-activated protein kinase or c-Jun N-terminal kinase (SAPK/JNK) signaling pathway and involves caspase activation.…”

Section: Introductionmentioning

confidence: 99%

Caspase-3 antisense oligodeoxynucleotides inhibit apoptosis in γ-irradiated human leukemia HL-60 cells

Zhang

Song

et al. 2007

Apoptosis

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To study the inhibitory effects of caspase-3 mRNA antisense oligodeoxynucleotides (ASODNs) on apoptosis, we designed four ASODNs targeting different regions of caspase-3 mRNA and transfected them into human leukemia HL-60 cells. The transfected cells were given 10 Gy gamma-irradiation followed by incubation for 18 h and measurement of apoptosis and caspase-3 expression. Our results showed that ASODN-2 targeting the 5' non-coding region of sites -62 to -46, and ASODN-3 targeting the 5' coding region of sites -1 to 16, both reduced apoptosis measured by gel electrophoresis and flow cytometry. Hoechst 33258 staining and TUNEL assay revealed that apoptotic indexes in the ASODN-2 and ASODN-3 groups were significantly lower than those in the untransfected and mismatched oligodeoxynucleotide (MODN) groups. Immunocytochemistry, Western blotting and RT-PCR showed that expression levels of caspase-3 protein and mRNA in both ASODN-2 and ASODN-3 groups were decreased compared with those in the untransfected and MODN groups. In conclusion, caspase-3 mRNA ASODNs can inhibit gamma-radiation-induced apoptosis of HL-60 cells and reduce expression of caspase-3 protein and mRNA. The results suggest that antisense approach may be useful for therapeutic treatment of certain neurodegenerative diseases in which apoptosis is involved.

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“…It has an integral role in a number of cellular processes, including cell cycle arrest, apoptosis, angiogenesis, and cellular differentiation [6,7]. P53 is implicated in the genesis of a variety of malignancies including brain tumors.…”

mentioning

confidence: 99%