Paraptosis

The first reported use of the term "paraptosis" was by Sabina Sperandio et al. in 2000. The group used human insulin-like growth factor 1 receptor (IGF-1R) to stimulate cell death in 293T cells and mouse embryonic fibroblasts, observing distinct differences from other forms of cell death. They coined the term "paraptosis", derived from the Greek preposition para, meaning beside or related to, and apoptosis. 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. ==Morphology==

Paraptosis is a form of type III programmed cell death with a unique combination of certain apoptotic and necrotic characteristics. Paraptosis does not demonstrate nuclear fragmentation, formation of apoptotic bodies, or definitive demonstration of chromatin condensation - all seen in apoptosis. Instead, paraptosis displays a somewhat primitive cell death path, comparable to necrosis, including characteristic cytoplasmic vacuole formation and late mitochondrial swelling The number and size of vacuoles increases over time. Eventually, the vacuole sizes reach a point of no return and the cell cannot recover. Paraptosis morphology changes are similar to the morphological changes undergone during the development of the nervous system. (2) heat shock proteins and (3) various other proteases. These substances are "danger signals" and result in inflammation. ==Pathway==

While certain templates of programmed cell death have been known to rely on de novo protein synthesis, paraptotic cell death induced by IGFIR-IC in 293T cells is deterred by actinomycin D and cycloheximide, thus demonstrating a dependence on transcription and translation. AIP1/Alix was determined to be "the first specific inhibitor" of paraptosis. Differences from other cell death pathways Cell death induced by IGFIR-IC in 293T cells demonstrated cell death without associated caspase activity. This is in comparison to apoptosis, in which the proapoptotic protein Bax induced caspase activation and cell death. Additionally, research found that caspase inhibitors (zVAD.fmk, p53, BAF), x-chromosome-linked inhibitor (xiap), and Bcl-xL( from the Bcl-2 family) did not prevent cell death in 293T cells when induced by IGFIR-IC. Therefore, paraptosis was concluded to differ from apoptosis (cell death type 1) in being unaffected by inhibitors of apoptosis. The most defining difference observed (as of April 2014) between paraptosis and autophagic cell death (cell death type 2) is paraptosis' lack of the characteristic autophagic vacuoles seen in autophagic cell death. As expected, autophagic cell death inhibitors (for instance, 3-methyladenine) are ineffective at inhibiting paraptosis. ==Comparison of cell death types==

Cells experience both morphologic and proteome changes when undergoing paraptosis. Changes to structural, signal transduction, and mitochondrial proteins have all been observed during paraptosis. 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. ==Potential medical significance==

Cancers Many anti-cancer substances have been shown to cause paraptosis in a large range of human cancer cells. This includes several compounds derived from natural sources Paraptosis is also an area of interest for Cancer Research as a way to treat apoptosis resistant cancers. 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. 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. 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. 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 cytotoxic 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. IGF-1R is an important area of research for neurodegenerative diseases, as defects in IGF-1R signaling, including increased levels of IGF-1R, have been found in the brains of Alzheimer's patients. ==Other examples==

Paraptosis-like programmed cell death has been observed in both plants and protists. Apoptotic death similar to that found in animals does not occur in plants, due to the cell wall of plant cells preventing phagocytosis. In an experiment with tobacco, bleomycin was used to introduce double strand breaks in the cells' DNA. This then caused cells to undergo programmed cell death with considerable vacuolization and an absence of DNA fragmentation and caspase inhibition, similar to paraptosis. A study with the algae Dunaliella viridis demonstrated the ability of protists to undergo programmed cell death via several types, including paraptosis and apoptosis, depending on different environmental stimuli. A combination of these factors have led to speculation that paraptosis may be an ancestral form of programmed cell death, conserved across different forms of life. ==See also==