Chemotherapy drugs induce pyroptosis through caspase-3 cleavage of a gasdermin

Yupeng Wang, Wenqing Gao, Xuyan Shi, Jingjin Ding, Wang Liu, Huabin He, Kun Wang & Feng Shao

Nature 547, 99–103 (06 July 2017)

Speaker: Ka Fu Lei (李嘉芙)                                                        Time: 13:00~14:00, Oct. 25, 2017

Commentator: Chih-Peng Chang , Ph.D(張志鵬 老師)             Place: Room 601

Abstract:

        Apoptosis is the programmed cell death which maintains the healthy survival/death balance in metazoan cells.¹ Caspase-3, a caspase protein that interacts with caspase-8 and caspase-9, plays a central role in the execution-phase of cell apoptosis. Pyroptosis shared some characteristics with apoptosis, including DNA fragmentation, nuclear condensation, and caspase dependence.² It can be induced by inflammatory caspases (caspase-1, -4, -5, -11), which cleave gasdermin D(GSDMD) and form pores on the cell member. Aberrant activation of pyroptosis may lead to sepsis and septic shock. The function and mechanisms of activation of other gasdermin family are still unclear. Here, author shows that GSDME (DFNA5), a family member of gasdermin which cleaved by caspase-3, can switch caspase-3-mediated apoptosis induced by TNF or chemotherapy drugs to pyroptosis. Notably, low level of GSDME showed evident apoptotic morphology and subsequent lysis before pyroptosis developed. It seems that high expression of GSDME is required to override the appearance of apoptosis in caspase-3-activated cells. Chemotherapy drugs are known to kill cells by activating caspase-3-mediated apoptosis. Their results showed that GSDME-positive cells underwent pyroptotic death after treated with chemotherapy drugs such as topotecan and etoposide while GSDME-negative cells developed apoptotic responses. GSDME seems to play an important role in chemotherapy drug-induced toxicity. Author suggested that these finding may offer new insights into cancer chemotherapy.

References:

1.      Mohamed Hassa, BioMed Research International, Volume 2014, Article ID 150845, 23 pages. Apoptosis and Molecular Targeting Therapy in Cancer

2.      Ine Jorgensen and Edward A Miao, Immunol Rev. 2015 May ; 265(1): 130–142. Pyroptotic cell death defends against intracellular pathogens