Cold atmospheric plasma induces GSDME-dependent pyroptotic signaling pathway via ROS generation in tumor cells

Abstract

Cold atmospheric plasma (CAP) has been proposed as a novel promising anti-cancer treatment modality. Apoptosis and necrosis have been revealed in CAP-induced cell death, but whether CAP induces pyroptosis, another kind of programmed cell death is still unknown. In the present study, we first reported that CAP effectively induced pyroptosis in a dose-dependent manner in Gasdermin E (GSDME) high-expressed tumor cell lines. Interestingly, the basal level of GSDME protein was positively correlated with the sensitivity to CAP in three selected cancer cell lines, implying GSDME might be a potential biomarker of prognosis in the forthcoming cancer CAP treatment. Moreover, our study revealed that CAP-induced pyroptosis depended on the activation of mitochondrial pathways (JNK/cytochrome c/caspase-9/caspase-3) and the cleavage of GSDME but not Gasdermin D (GSDMD). ROS generation induced by CAP was identified to initiate the pyroptotic signaling. These results complemented our knowledge on CAP-induced cell death and provide a strategy to optimize the effect of CAP cancer treatment.

Pyroptosis: a new paradigm of cell death for fighting against cancer

“…Local treatment with H-FIRE not only ablates the primary tumor, but also reduces metastatic lesions, which is dependent on the adaptive immune system [ 130 ]. Recently, Xiaorui et al reported that cold atmospheric plasma, a novel promising anti-cancer treatment, induces GSDME-dependent pyroptotic cell death in GSDME-expressing tumor cells [ 131 ].…”

Intracellular Responses Triggered by Cold Atmospheric Plasma and Plasma-Activated Media in Cancer Cells

“…In contrast to apoptosis-cell death without any inflammatory outcome-cell death mechanisms that inherently result in inflammation are pyroptosis and immunogenic cell death (ICD). Recently, CAP was shown to induce pyroptosis, another highly inflammatory programmed cell death, via ROS generation in gasdermin E expressing tumour cell lines [114]. The basal level of gasdermin E protein positively correlates with the cell's sensitivity to CAP-induced pyroptosis, which depends on the activation of mitochondrial pathways (JNK/cytochrome c/caspase-9/caspase-3) and the cleavage of gasdermin E [114].…”

“…Recently, CAP was shown to induce pyroptosis, another highly inflammatory programmed cell death, via ROS generation in gasdermin E expressing tumour cell lines [114]. The basal level of gasdermin E protein positively correlates with the cell's sensitivity to CAP-induced pyroptosis, which depends on the activation of mitochondrial pathways (JNK/cytochrome c/caspase-9/caspase-3) and the cleavage of gasdermin E [114]. ICD, on the other hand, involves changes in the composition of the cell surface, as well as the release of soluble mediators, which operate on a series of receptors expressed by dendritic cells, to stimulate the presentation of tumour antigens to T cells and elicit tumour cell death [115].…”

Chemical mechanisms of non-thermal plasma action on cells

“…Так, перекись водорода и свободные радикалы вызывают снижение митохондриального мембранного потенциала, высвобождение апоптоз-индуцирующего фактора в цитозоль, снижают экспрессию антиапоптотических белков в митохондриях [59,67]. Повреждение митохондрий может быть ответственно и за развитие пироптоза за счет механизмов, утилизирующих высвобождение цитохрома с, активацию каспазы-9 и каспазы-3 [68]. Кроме того, аккумуляция активных форм кислорода в митохондриях, вызванная действием бесклеточной питательной среды, обработан-ной ХП, предшествует развитию аутофагии и митофагии в клетках [59].…”