Abstract
BackgroundPyroptosis is a lytic cell death form executed by gasdermins family proteins. Induction of tumor pyroptosis promotes anti-tumor immunity and is a potential cancer treatment strategy. Triptolide (TPL) is a natural product isolated from the traditional Chinese herb which possesses potent anti-tumor activity in human cancers. However, its role in pyroptosis remains to be elucidated.MethodsCell survival was measured by colony formation assay. Cell apoptosis was determined by Annexin V assay. Pyroptosis was evaluated by morphological features and release of interleukin 1β and lactate dehydrogenase A (LDHA). Immunofluorescence staining was employed to measure subcellular localization of proteins. Tumorigenicity was assessed by a xenograft tumor model. Expression levels of mRNAs or proteins were determined by qPCR or western blot assay, respectively.ResultsTriptolide eliminates head and neck cancer cells through inducing gasdermin E (GSDME) mediated pyroptosis. Silencing GSDME attenuates the cytotoxicity of TPL against cancer cells. TPL treatment suppresses expression of c-myc and mitochondrial hexokinase II (HK-II) in cancer cells, leading to activation of the BAD/BAX-caspase 3 cascade and cleavage of GSDME by active caspase 3. Silencing HK-II sensitizes cancer cells to TPL induced pyroptosis, whereas enforced expression of HK-II prevents TPL induced pyroptosis. Mechanistically, HK-II prevents mitochondrial translocation of BAD, BAX proteins and activation of caspase 3, thus attenuating cleavage of GSDME and pyroptosis upon TPL treatment. Furthermore, TPL treatment suppresses NRF2/SLC7A11 (also known as xCT) axis and induces reactive oxygen species (ROS) accumulation, regardless of the status of GSDME. Combination of TPL with erastin, an inhibitor of SLC7A11, exerts robust synergistic effect in suppression of tumor survival in vitro and in a nude mice model.ConclusionsThis study not only provides a new paradigm of TPL in cancer therapy, but also highlights a crucial role of mitochondrial HK-II in linking glucose metabolism with pyroptosis.
Highlights
Pyroptosis is a lytic cell death form executed by gasdermins family proteins
This study provides a new paradigm of TPL in cancer therapy, and highlights a crucial role of mitochondrial HK-Hexokinase II (II) in linking glucose metabolism with pyroptosis
TPL induced pyroptotic cell death in head and neck cancer cells To assess the effect of TPL on head and neck cancer cell lines, we initially treated diverse cancer cell lines with 0–150 nM TPL
Summary
Pyroptosis is a lytic cell death form executed by gasdermins family proteins. Induction of tumor pyroptosis promotes anti-tumor immunity and is a potential cancer treatment strategy. Pyroptosis is a pro-inflammatory form of regulated cell death. In addition to bacterial infection, non-bacterial pyroptosis occurs in epithelial cells upon various death stimuli. Pyroptosis is executed by gasdermins, a poreformation proteins family [11]. The caspases cleave gasdermins in its linker and liberate the cytotoxic N-terminal domain, which initiates pyroptosis by forming pores in cell membrane [12,13,14]. Gasdermin E (GSDME) is a potent tumor suppressor and has the potential to evoke anti-tumor immunity through mediating pyroptosis in cancer cells [15]
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