Investigation of P2X7 mediated phagocytosis - potential therapeutic target for cancer treatment
The P2X7 receptor was originally recognized as an ion channel for influx of Ca2+, Mg2+ and efflux of K+.
Following its activation by extracellular ATP, it triggers a number of downstream pro-inflammatory responses including IL-1β, IL-18 and formation of inflammasome. Prolonged exposure to ATP (over 30 seconds) opens large pores on the cell membrane and eventually leads to apoptotic death of cells. Recent discoveries from Dr. Ben Gu’s group have demonstrated that P2X7 is also a scavenger receptor in the absence of ATP, while ATP normally dissociates P2X7 from its cytoskeletal attachment with nonmuscle myosin heavy chain IIA (also known as myosin 9) and inhibits P2X7 mediated phagocytosis. Therefore, it is clear that P2X7 has a dual functional mode: an ion channel to form pores triggering pro-inflammatory responses in the presence of ATP, and a scavenger receptor to clear apoptotic cells and cell debris in the absence of ATP. Interestingly, the cancer cell-expressed P2X7 has been found in a non-functional conformation, rending them unable to form apoptotic pores, which prevent cancer cells from undergoing programmed cell death. Moreover, non-functional P2X7 keep tumor cells highly phagocytic even in the presence of ATP. A specific antibody against non-functional P2X7 receptors, which was found to recognize tumor cells from solid tumors, has become an unique biomarker and therapeutic reagent for various solid tumors. Its therapeutic values are currently explored clinically by the Biosceptre Pty Ltd (Cambridge, UK). In this study, we will characterize the non-functional P2X7 on the surface of tumor cells and further investigate whether and how the uncontrolled P2X7-mediated phagocytosis contributes to the uncontrolled proliferation of tumor cells. Different strategies will be used to search for inhibitors for P2X7 mediated phagocytosis. The outcomes will lead to better understanding of oncogenesis and a possible novel treatment for solid tumor.
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