Editors' ChoiceCancer

Chemotherapy-treated cells go up in flames

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Science Translational Medicine  17 May 2017:
Vol. 9, Issue 390, eaan4289
DOI: 10.1126/scitranslmed.aan4289

Abstract

Apoptosis induced by chemotherapies can also trigger proinflammatory pyroptosis.

Pyroptosis is the canonical proinflammatory form of programmed cell death induced by intracellular pathogens and critical for the mounting of an antimicrobial response. In contrast, apoptosis has, historically, been viewed as an immunologically silent process by which cells die due to superfluity or irreparable damage, much like that induced by cytotoxic chemotherapies. The lack of inflammation associated with apoptosis is of vital physiological importance because this form of cell death is responsible for the normal clearance of billions of cells within the human body each day. However, recent work from several laboratories has demonstrated that apoptosis can sometimes trigger inflammation via processes that are incompletely understood.

Wang et al. now demonstrate that cell death induced by chemotherapeutic agents can switch from an apoptotic to a pyroptotic phenotype via a caspase-dependent process. Specifically, the caspase 3 protease, which is activated during apoptotic cell death, can cleave a newly-identified member of the gasdermin family (GSDME, previously identified as DFNA5). This cleavage removes an autoinhibitory domain and activates the pore-forming activity of GSDME, promoting permeabilization of the plasma membrane and disruption of osmotic potential, which results in cell swelling and eventual lysis. The lysis of the cell is a key step in pyroptosis because it releases proinflammatory signals that stimulate the recruitment of additional immune cells. This report demonstrates that apoptosis-inducing chemotherapies are capable of activating proinflammatory cell death, yet it goes on to show that this is largely true in healthy tissues but not all cancers, which sometimes silence GSDME. To demonstrate the importance of this pathway in healthy tissues, the authors show that Gsdme–/– mice exhibit reduced toxicities after chemotherapy treatment as a result of their impairment in the apoptosis-pyroptosis switch.

Based on these findings, it would be expected that certain cancer immunotherapies would be more effective in GSDME-expressing cancers because these tumors would be more likely to support a proinflammatory response, especially when treated with apoptosis-inducing therapies. Notably, several treatments have recently been shown to directly elevate GSDME expression in cancer cells, which could also enhance antitumor immune responses. Last, inhibition of GSDME may attenuate the cytotoxic effects of chemotherapy in healthy tissues.

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