Team Identifies Key Driver of Cancer Cell Death Pathway that Activates Immune Cells
Published:26 Aug.2023 Source:University of Illinois at Urbana-Champaign, News Bureau
Scientists have identified a protein that plays a pivotal role in the action of several emerging cancer therapies. The researchers say the discovery will likely aid efforts to fine-tune the use of immunotherapies against several challenging cancers.
TRPM4 is the first protein mediator of anticancer therapy-induced necrosis to be described, Shapiro said. In previous work, Shapiro, U. of I. chemistry professor and study co-author Paul Hergenrother and their colleagues developed two drugs -- a compound called BHPI and later, a more effective agent known as ErSO -- that spur necrosis in solid tumors, dramatically shrinking and often eradicating primary and metastatic tumors in mice. These drugs work by binding to estrogen receptors on cancer cells and pushing a normally protective cellular stress-response pathway into overdrive. This pathway, the "anticipatory unfolded protein response, or a-UPR," ultimately causes the cell to swell, leak and die.
To identify the relevant proteins, Shapiro and his colleagues screened breast cancer cells. The researchers were surprised to find that TRPM4 emerged as a key driver of the process of necrosis in cancer cells treated with ErSO and BHPI. The team also found that TRPM4 was important for the activity of several other necrosis-inducing cancer therapies. Further study revealed that an ErSO-induced increase in intracellular calcium causes the TRPM4 channel to open, allowing sodium ions and water to flow into the cell. The influx causes the cell to swell, rupture and leak, activating immune cells and causing them to rush to the site of the dead cells.