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Paraptosis (from the Ancient Greek παρά para, "related to" and apoptosis) is a type of programmed cell death, morphologically distinct from apoptosis and necrosis. The defining features of paraptosis are Vacuole, independent of caspase activation and inhibition, and lack of apoptotic morphology. Paraptosis lacks several of the hallmark characteristics of apoptosis, such as membrane blebbing, chromatin condensation, and nuclear fragmentation. Like apoptosis and other types of programmed cell death, the cell is involved in causing its own death, and gene expression is required. This is in contrast to necrosis, which is non-programmed cell death that results from Cell damage to the cell.
Paraptosis has been found in some developmental and neurodegenerative cell deaths, as well as induced by several cancer drugs.
Paraptosis was not recognized as a form of cell death by the Nomenclature Committee on Cell Death in their 2018 review article. The use of this term was explicitly discouraged by the Committee in their 2012 revision
While Sperandio was the first to publish the term paraptosis, this was not the first time cell death with the properties of paraptosis was observed. Terms such as "cytoplasmic" and "type 3 cell death" had previously been used to describe these forms of cell death. These forms are very similar to paraptosis morphologically, and it is possible that some instances of cell death originally described as one of these forms are occurrences of paraptosis.
Similar to apoptosis, staining techniques can be used to identify paraptotic cells by highlighting the translocation of phosphatidylserine from the plasma membrane cytoplasmic (inner) leaflet to the cell surface or outer leaflet.
Paraptosis morphology changes are similar to the morphological changes undergone during the development of the nervous system.
Induction of paraptosis has been determined to be mediated through two positive signal transduction pathways, MAPK and JNK, by using IGF-IR at the receptor level. As such, paraptosis can be prevented by inhibiting specific of these pathways.
AIP1 interaction (via its C-terminus) with endophilins can induce intracellular vacuole formation. AIP1/Alix was determined to be "the first specific inhibitor" of paraptosis.
Paraptosis-like phenotype has also been described in human colorectal cancer cells following overactivation of the non-receptor tyrosine kinase c-Src suggesting potential involvement of Src-signalling in paraptosis.
In apoptosis, HMGB1, a chromatin protein, is retained within the nucleus to result in formations of apoptotic bodies, while in paraptosis HMGB1 is released.
The most defining difference observed (as of April 2014) between paraptosis and Autophagy cell death (cell death type 2) is paraptosis' lack of the characteristic autophagic vacuoles seen in Autophagy cell death. As expected, autophagic cell death inhibitors (for instance, 3-methyladenine) are ineffective at inhibiting paraptosis.
| + Summary of differences between cell death pathways ! !! Paraptosis !! Apoptosis !! Necrosis |
| Yes |
| No |
| No |
| No |
| Yes |
| Yes, late |
| No |
| Sometimes |
| No |
| No |
| No |
| No |
| Usually not |
Mitochondrial staining reveals that rounded paraptotic cells with elevated levels of prohibitin appear to be undergoing reorganization of the mitochondrial network.
Paraptotic cells demonstrated a 3.4 fold increased in prohibitin. Increased levels of prohibitin in conjugation with a paraptotic stimulus can result in cell death that is unable to be inhibited by caspase inhibitors.
Paclitaxel, commonly distributed under the trade name Taxol, is a cancer drug used for the treatment of breast and ovarian cancers. At high concentrations (70 μM), one study showed it to induce a paraptosis-like cell death, and could be an important mechanism for treating apoptosis-resistant cancers.
Researchers have reported finding that Tocotrienol, a form of vitamin E derived from palm oil, induced paraptosis-like cell death in colon cancer cells. Along with inducing paraptosis, γ-tocotrienol also suppressed the Wnt signaling pathway, which plays a role in tumor development. The combination of these two features could provide a novel mechanism for treating colon cancer.
Steamed American ginseng extract has been reported to "potently kill colorectal cancer cells". Specifically, derivatives of protopanaxadiol Rg3 and Rh2, are the key ginsenosides found in the extract. In colorectal cancer cell lines, HCT116, cytosolic vacuolization has been induced by Rh2. Furthermore, Rh2-induced vacuolization was inhibited by a MEK1/2 specific inhibitor U0126, cycloheximide, thus confirming two characteristic properties of paraptosis, signaling via MAP kinase and required protein translation. Rh2 also induces increase ROS levels, which activate the NF-κB signaling pathway, while blocking ROS with Acetylcysteine or catalase prevents the activation of NF-κB signaling and further enhances cell death induced by Rh2. This suggests an antioxidant-enhanced anticancer effect of Rh2.
Honokiol, a compound derived from Magnolia officinalis, can induce paraptosis in human leukemia cells. In the NB4 cell line, paraptosis was the primary method of cell death. In K562 cells, apoptosis was the primary mechanism, with paraptosis occasionally found. Researchers stated that this suggests that leukemia cell death can be induced by multiple pathways.
In one experiment a phosphine copper(I) complex caused paraptosis in colon cancer cells by inducing endoplasmic reticulum stress. Another copper complex, the A0 thioxotriazole copper (II) complex, also caused paraptosis in HT1080 fibrosarcoma cells via endoplasmic reticulum stress and cytoplasmic vacuolization. Along with Cytotoxicity effects such as an increase in oxidized glutathione and prevention of proteasome activity, A0 prevented the activity of caspase-3, which may inhibit apoptosis and cause the cells to die via paraptosis.
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