Gasdermins and pannexin-1 mediate pathways of chemotherapy-induced cell lysis in hematopoietic malignancies

Abstract

Pyroptosis is a mechanism of programmed, necrotic cell death mediated by gasdermins, a family of pore-forming proteins. Caspase-1 activates gasdermin D (GSDMD) under inflammatory conditions, whereas caspase-3 activates GSDME under apoptotic conditions, such as those induced by chemotherapy. These pathways are thought to be separate. However, we found that they are part of an integrated network of gatekeepers that enables pyroptotic cell death. We observed that GSDMD was the primary pyroptotic mediator in cultured blood cells in response to doxorubicin and etoposide, two common chemotherapies for hematopoietic malignancies. Upon treatment, the channel protein pannexin-1 (PANX1), which is stimulated by the initiation of apoptosis, increased membrane permeability to induce K + efflux-driven activation of the NLRP3 inflammasome and GSDMD. However, either PANX1 or GSDME could also be the primary mediator of chemotherapy-induced pyroptosis when present at higher amounts. The most abundant pore-forming protein in acute myeloid leukemias from patients predicted the cell death pathway in response to chemotherapy. This interconnected network, a multistep switch that converts apoptosis to pyroptosis, could be clinically titratated to modulate cell death with regard to antitumor immunity or tumor lysis syndrome in patients. The channel PANX-1 initiates or collaborates in enabling chemotherapy-induced lytic cell death. In response to chemotherapy, the induction of apoptotic cell death can be converted to a form of lytic cell death called pyroptosis through the pore-forming protein gasdermin E, which can trigger an antitumor immune response. Zhou et al . uncovered alternate pathways to chemotherapy-induced pyroptosis. Although a high abundance of gasdermin E had a dominant effect, the conversion to pyroptosis in human myeloid cells could independently be mediated by the channel pannexin-1 (PANX1), either through the induction of an alternate pyroptotic pathway dependent on gasdermin D or independently of gasdermins. In blood and bone marrow biopsies from leukemia patients, the relative abundance of gasdermin E, gasdermin D, and PANX1 predicted the pathway that mediated pyroptotic cell death in response to doxorubicin. The findings reveal the multiple pathways that lead to this form of chemotherapy-induced cell death and may inform treatment strategies in cancer patients.—LKF