What do we say to apoptosis? Not today!

Have you ever wondered if there is any way to bring back the dead? And if resurrected, will they be the same person or become a zombie (the question which actually made Pet cemetery scary and GOT interesting)? Just like humans, for a long time, it was believed that when a cell dies, there is no coming back. “The undiscovered country from whose bourn no traveller returns “, Hamlet act 3, scene 1. Easter is the celebration of the resurrection of Jesus, and on this occasion, we at Antibuddies ought to make you aware of something similar – resurrection of cells. How is that possible? Glad you asked!

Anastasis- The cellular Night King

Apoptosis is a well-known form of programmed cell death(Kerr et al., 1972). In 2012, Tang et. al. discovered that cell death may not be as black and white as we might have learned. Contrary to apoptosis (“falling to death” in Greek), anastasis (“rising to life” in Greek) refers to the mechanism that arrests and reverses programmed cell death and rescues cells from dying (Tang et al., 2012).

Tang et. al. (Tang et al., 2012) induced lethal dose of apoptotic stimulus (e.g. ethanol) and observed cell shrinkage, membrane blebbing, mitochondrial fragmentation, nuclear condensation, executioner caspase enzyme activation and DNA damage- hallmarks of apoptosis (Kerr et al., 1972). But, when they withdrew the stimulus, apoptotic mechanisms were reversed, and majority of the cells survived. Several molecular mechanisms are needed to reverse apoptosis: 1. suppress the apoptosis, 2. remove the proteins cleaved in apoptosis, and 3. repair the damage occurred (Tang et al., 2013). Anastasis happens in two stages- early and late. Early stage includes a stress response and re-entry in the cell cycle; and late stage comprise enhancing of proliferation, migration, angiogenesis and epithelial-mesenchymal transition (Sun et al., 2017). Some of the molecular players in anastasis are Bcl-2 (pro-survival protein), heat shock proteins (suppressing execution caspase activation) and proteins involved in DNA damage repair (Tang et al., 2012). Cells going through anastasis do not always go back to how they were, some of them were reported to have increase in chromosomal aberration (Tang et al., 2012).

Anastasis was demonstrated in a variety of normal and cancer cell types, like primary liver and heart cells, macrophages, fibroblasts, brain cells (Tang et al., 2012) and in living organisms like Caenorhabditis elegans (Reddien et al., 2001). Why didn’t scientist notice anastasis sooner? Dying cells mostly regain their normal morphology and repair the damage quickly and hence, are difficult to distinguish from live cells (Tang et al., 2013). The best way to detect anastasis, according to Tang et. al is to continuously monitor cells throughout the processes of apoptosis and anastasis with time-lapse fluorescence microscopy (Tang et al., 2012, 2013). Newer method would include CasExpress, a biosensor that marks cells that have survived the executioner- caspase (caspase-3) activation (Ding et al., 2016).

Anastasis: a boon or a curse?

Evolutionarily, the purpose of anastasis could be to limit the permanent tissue damages which result after severe chemical, physical or physiological injury (Sun et al., 2017). If you watched the Netflix show Snowpiercer, think it this way: since earth froze, scientists wanted to make a “super-human” whose body could surpass the lethal shock from ice cold surroundings, creating “Icy Bob”. The positive outcome of anastasis would be the preservation of cells which are usually difficult to replace, such as mature neurons and heart cells (Tang et al., 2012).

However, there is a negative connotation to this story; researchers noticed some of the anastasis consequences like resisting apoptosis and inducing angiogenesis belong to hallmarks of cancer (Hanahan & Weinberg, 2011). Anastasis may contribute to metastasis of tumour cells because it increases migratory levels of the cells. Moreover, tumour cells can relapse after anticancer treatments and acquire new mutations, transforming them into more aggressive and metastatic cancer cells (Tang et al., 2012). In apoptosis, cells release mRNA and cancer cells were believed to utilize that mRNA, on the other hand in anastasis cancer cells could be using its own stored mRNA for recovery as an additional energy source (Raj et al., 2019).

Is anastasis the only savior of cells?

Apoptosis represents the most conventional way of cell death, but there are some unconventional ways as well. And evidence suggests that cells murdered by other weapons can be resurrected too! In 2017 resuscitation was discovered as recovery from programmed version of necrosis (injury activated inflammatory cell death) known as necroptosis (Gong et al., 2017). Entosis, another form of cell death where one live cell swallows the other is also reversible (Overholtzer & Brugge, 2008). At Antibuddies, we wonder if pyroptosis (inflammatory form of programmed cell death (Gudipaty et al., 2018)) could also be reversed?

Food for thought

Potential of cells to resurrect surely presents an unexpected outcome. What is the scientific meaning of coming back to life? How can we define cell death if they can become alive again? Are those cells zombies or were they never actually dead? Can there be some way to never let any cells die? Can this be the plot of a next super-villain movie? We can already speculate the ways it can be used in cancer research and as potential treatments. Even though the name “zombie cell theory” sounds fun, these cells show no craving for our brains, so we can wave that theory goodbye (for now).

Sources:

• Ding, A. X., Sun, G., Argaw, Y. G., Wong, J. O., Easwaran, S., & Montell, D. J. (2016). CasExpress reveals widespread and diverse patterns of cell survival of caspase-3 activation during development in vivo. ELife, 5. https://doi.org/10.7554/eLife.10936
• Gong, Y.-N., Guy, C., Olauson, H., Becker, J. U., Yang, M., Fitzgerald, P., Linkermann, A., & Green, D. R. (2017). ESCRT-III Acts Downstream of MLKL to Regulate Necroptotic Cell Death and Its Consequences. Cell, 169(2). https://doi.org/10.1016/j.cell.2017.03.020
• Gudipaty, S. A., Conner, C. M., Rosenblatt, J., & Montell, D. J. (2018). Unconventional Ways to Live and Die: Cell Death and Survival in Development, Homeostasis, and Disease. Annual Review of Cell and Developmental Biology, 34(1). https://doi.org/10.1146/annurev-cellbio-100616-060748
• Hanahan, D., & Weinberg, R. A. (2011). Hallmarks of cancer: The next generation. In Cell (Vol. 144, Issue 5, pp. 646–674). https://doi.org/10.1016/j.cell.2011.02.013
• Kerr, J. F. R., Wyllie, A. H., & Currie, A. R. (1972). Apoptosis: A Basic Biological Phenomenon with Wideranging Implications in Tissue Kinetics. British Journal of Cancer, 26(4). https://doi.org/10.1038/bjc.1972.33
• Overholtzer, M., & Brugge, J. S. (2008). The cell biology of cell-in-cell structures. Nature Reviews Molecular Cell Biology, 9(10). https://doi.org/10.1038/nrm2504
• Raj, A. T., Kheur, S., Bhonde, R., Gupta, A. A., Patil, V. R., & Kharat, A. (2019). Potential role of anastasis in cancer initiation and progression. Apoptosis, 24(5–6). https://doi.org/10.1007/s10495-019-01538-8
• Reddien, P. W., Cameron, S., & Horvitz, H. R. (2001). Phagocytosis promotes programmed cell death in C. elegans. Nature, 412(6843). https://doi.org/10.1038/35084096
• Sun, G., Guzman, E., Balasanyan, V., Conner, C. M., Wong, K., Zhou, H. R., Kosik, K. S., & Montell, D. J. (2017). A molecular signature for anastasis, recovery from the brink of apoptotic cell death. Journal of Cell Biology, 216(10), 3355–3368. https://doi.org/10.1083/jcb.201706134
• Tang, H. L., Tang, H. M., Mak, K. H., Hu, S., Wang, S. S., Wong, K. M., Wong, C. S. T., Wu, H. Y., Law, H. T., Liu, K., Talbot, C. C., Lau, W. K., Montell, D. J., & Fung, M. C. (2012). Cell survival, DNA damage, and oncogenic transformation after a transient and reversible apoptotic response. Molecular Biology of the Cell, 23(12), 2240–2252. https://doi.org/10.1091/mbc.E11-11-0926
• Tang, H. L., Tang, H. M., & Montell, D. J. (2013). Stress Induced Mutagenesis, Genetic Diversification, and Cell Survival via Anastasis, the Reversal of Late Stage Apoptosis. In Stress-Induced Mutagenesis. Springer New York. https://doi.org/10.1007/978-1-4614-6280-4_11

Check out the Easter special article on Antibuddies blog: “What do we say to apoptosis? Not today!”

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