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

Area of Science:

• Cell Biology
• Immunology
• Oncology

Background:

• Pyroptosis is a programmed cell death mechanism executed by gasdermins.
• Caspase-1/GSDMD and Caspase-3/GSDME pathways are traditionally viewed as distinct.
• Chemotherapy can induce apoptosis or pyroptosis, impacting cancer treatment outcomes.

Purpose of the Study:

• To investigate the interplay between apoptosis and pyroptosis pathways.
• To identify key mediators of chemotherapy-induced cell death.
• To explore the clinical potential of modulating cell death pathways.

Main Methods:

• Utilized cultured blood cells and patient-derived acute myeloid leukemia samples.
• Administered chemotherapeutic agents like doxorubicin and etoposide.
• Analyzed the roles of gasdermin D (GSDMD), gasdermin E (GSDME), and pannexin-1 (PANX1) in cell death.

Main Results:

• Gasdermin D (GSDMD) was the primary pyroptosis mediator in response to chemotherapy.
• Pannexin-1 (PANX1) activation during apoptosis triggers K+ efflux, activating NLRP3 inflammasome and GSDMD.
• PANX1 or GSDME could act as primary mediators depending on their abundance.
• The predominant pore-forming protein predicted the cell death pathway in acute myeloid leukemia.

Conclusions:

• Chemotherapy-induced pyroptosis involves an integrated network switching from apoptosis.
• This interconnected network offers a potential target for modulating antitumor immunity and tumor lysis syndrome.
• Clinical titration of this network could personalize cancer therapy.