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Caspase-dependent cell death-associated release of nucleosome and damage-associated molecular patterns.

ABSTRACT: Apoptosis, which is anti-inflammatory, and necrosis, which is pro-inflammatory, represent the extremes of the cell death spectrum. Cell death is complex and both apoptosis and necrosis can be observed in the same cells or tissues. Here, we introduce a novel combined mode of cellular demise--caspase-dependent regulated necrosis. Most importantly, it is mainly characterized with release of marked amount of oligo- or poly-nucleosomes and their attached damage-associated molecular patterns (DAMPs) and initiated by caspase activation. Caspase-activated DNase has dual roles in nucleosomal release as it can degrade extracellularly released chromatin into poly- or oligo-nucleosomes although it prohibits release of nucleosomes. In addition, osmotically triggered water movement following Cl(-) influx and subsequent Na(+) influx appears to be the major driving force for nucleosomal and DAMPs release. Finally, Ca(2+)-activated cysteine protease, calpain, is an another essential factor in nucleosomal and DAMPs release because of complete reversion to apoptotic morphology from necrotic one and blockade of nucleosomal and DAMPs release by its inhibition.

SUBMITTER: Yoon S

PROVIDER: S-EPMC4649531 | biostudies-other | 2014

REPOSITORIES: biostudies-other

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Caspase-dependent cell death-associated release of nucleosome and damage-associated molecular patterns.

Yoon S S Park S J SJ Han J H JH Kang J H JH Kim J-h JH Lee J J Park S S Shin H-J HJ Kim K K Yun M M Chwae Y-J YJ

Cell death & disease 20141030

Apoptosis, which is anti-inflammatory, and necrosis, which is pro-inflammatory, represent the extremes of the cell death spectrum. Cell death is complex and both apoptosis and necrosis can be observed in the same cells or tissues. Here, we introduce a novel combined mode of cellular demise--caspase-dependent regulated necrosis. Most importantly, it is mainly characterized with release of marked amount of oligo- or poly-nucleosomes and their attached damage-associated molecular patterns (DAMPs) a ...[more]

PMID: 25356863

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Project description:BackgroundChemotherapeutics can stimulate immune antitumor response by inducing immunogenic cell death (ICD), which is activated by Damage-Associated Molecular Patterns (DAMPs) like the exposure of calreticulin (CRT) on the cell surface, the release of ATP and the secretion of High Mobility Group Box 1 (HMGB1).MethodsHere, we investigated the levels of ICD-associated DAMPs induced by chemotherapeutics commonly used in the clinical practice of non-small cell lung cancer (NSCLC) and the association of these DAMPs with apoptosis and autophagy. A549 human lung adenocarcinoma cells were treated with clinically relevant doses of cisplatin, carboplatin, etoposide, paclitaxel and gemcitabine. We assessed ICD-associated DAMPs, cell viability, apoptosis and autophagy in an integrated way.ResultsCisplatin and its combination with etoposide induced the highest levels of apoptosis, while etoposide was the less pro-apoptotic treatment. Cisplatin also induced the highest levels of ICD-associated DAMPs, which was not incremented by co-treatments. Etoposide induced the lower levels of ICD and the highest levels of autophagy, suggesting that the cytoprotective role of autophagy is dominant in relation to its pro-ICD role. High levels of CRT were associated with better prognosis in TCGA databank. In an integrative analysis we found a strong positive correlation between DAMPs and apoptosis, and a negative correlation between cell number and ICD-associated DAMPs as well as between autophagy and apoptosis markers. We also purpose a mathematical integration of ICD-associated DAMPs in an index (IndImunnog) that may represent with greater biological relevance this process. Cisplatin-treated cells showed the highest IndImmunog, while etoposide was the less immunogenic and the more pro-autophagic treatment.ConclusionsCisplatin alone induced the highest levels of ICD-associated DAMPs, so that its combination with immunotherapy may be a promising therapeutic strategy in NSCLC.

Dataset Information

Caspase-dependent cell death-associated release of nucleosome and damage-associated molecular patterns.

Publications

Caspase-dependent cell death-associated release of nucleosome and damage-associated molecular patterns.

Similar Datasets

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