Team:HZAU-China/Description
Backgroud about pyroptosis
Pyroptosis is a lytic form of inflammatory cell death which is induced by caspases 1, 3, 4, 5 and 11. The morpholog of pyroptosis is characterized by cell swelling which causes release of cytoplasmic contents of the cell, including proinflammatory cytokines, endogenous ligands, alarmins, ATP, and other danger-associated molecular patterns.1 A recent study reported that Gasdermin D is a essential effector of pyroptosis.2 Full length GasderminD can be cleave by Caspase when host cell defined the infection. Thus, the N-terminal of Gasdermin D named PTD(pore-forming domain) which can oligomerize to form pore on the plasm membrane is exposured from RD (repressor domain)3. subsequently, sodium and water rush into cell causes the cell swelling result in cell rupture. Simultaneously, IL-1β is released in to extracellular environment though the gasdermin pore4 (Fig 1).(找美工画)
Some recent studies demonstrated following points：
1.Berberin inhibits the viability of HepG2 cell though induction of pyroptosis5.
2.Caspase 1 rescure the sensitivity of radiant lethality in prostate cancer 6.
3.Nlrp3−/− mice are susceptible to colitis associated colon cancer7.
According to these studies, we think pyroptosis can be exploited for tumor suppression.
Significance
Recent study demonstrated that GSDME was expressed in many normal cells but silenced in most cancer cells. So chemotherapy drug activate caspase-3-mediated pyroptosis in normal tissue but caspase-3-mediated apoptosis in cancer cells result in high efficacy of tissue damage but low efficacy of tumor kill8. Our project can trigger pyroptosis in cancer cells through targeted vector in order to switch this process(Fig 2). .(找美工画)
What else, the lysate of cell rupture during pyroptosis destroy tumor microenvironment. Pyroptosis not only releases "find me" signal and "eat me" signal9. "Find me" signal such as ATP attracts immune cell into tummor bed. Pyroptosis induce greater ATP release than apoptosis. These signals attract immune cell into tummor bed. On the other hand, ATP bind to purinergic P2RX7 receptors on DC, thus activating the NLRP3/ASC/caspase-1 inflammasome and secreting interleukin-1β (IL-1β) which is required for CD8+ T cells to releasing IFNγ which lysis tumour cells10. During pyroptosis, phosphatidylserineexternalization as a "eat me" signal to recruit macrophage to engulf the tumor cells(Fig 3).(找美工画)
Reference
1 Kovacs, S. B. & Miao, E. A. Gasdermins: Effectors of Pyroptosis. Trends Cell Biol 27, 673-684, doi:10.1016/j.tcb.2017.05.005 (2017).
2 Shi, J. et al. Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death.Nature 526, 660-665, doi:10.1038/nature15514 (2015).
3 Ding, J. et al. Pore-forming activity and structural autoinhibition of the gasdermin family. Nature535, 111-116, doi:10.1038/nature18590 (2016).
4 Liu, X. et al. Inflammasome-activated gasdermin D causes pyroptosis by forming membrane pores. Nature 535, 153-158, doi:10.1038/nature18629 (2016).
5 Pyroptosis is involved in the pathogenesis of human hepatocellular carcinoma.(2016
).
6 Rachel N. Winter, A. K., Andrew Borkowski, and Natasha Kyprianou. Loss of Caspase-3 Protein Expression in Human Prostate Cancer. CANCER RESEARCH 61, 1227-1232 (2001).
7 Allen, I. C. et al. The NLRP3 inflammasome functions as a negative regulator of tumorigenesis during colitis-associated cancer. J Exp Med 207, 1045-1056, doi:10.1084/jem.20100050 (2010).
8 Wang, Y. et al. Chemotherapy drugs induce pyroptosis through caspase-3 cleavage of a gasdermin. Nature 547, 99-103, doi:10.1038/nature22393 (2017).
9 Wang, Q. et al. Pyroptotic cells externalize eat-me and release find-me signals and are efficiently engulfed by macrophages. Int Immunol 25, 363-372, doi:10.1093/intimm/dxs161 (2013).
10 Ghiringhelli, F. et al. Activation of the NLRP3 inflammasome in dendritic cells induces IL-1beta-dependent adaptive immunity against tumors. Nat Med 15, 1170-1178, doi:10.1038/nm.2028 (2009).