Natural product triptolide induces GSDME-mediated pyroptosis in head and neck cancer through suppressing mitochondrial hexokinase-ΙΙ.
Natural product triptolide induces GSDME-mediated pyroptosis in head and neck cancer through suppressing mitochondrial hexokinase-ΙΙ.
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天然产物雷公藤甲素通过抑制线粒体己糖激酶-α，诱导头颈癌中 GSDME 介导的细胞焦亡。
DOI：
10.1186/s13046-021-01995-7
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发表时间：
2021-06-09
期刊：
影响因子：
--
通讯作者：
Xiang B
中科院分区：
文献类型：
--
作者：
Cai J;Yi M;Tan Y;Li X;Li G;Zeng Z;Xiong W;Xiang B
热解是由gasdermins家族蛋白执行的裂解性细胞死亡形式。诱导肿瘤细胞凋亡可增强抗肿瘤免疫，是一种潜在的肿瘤治疗策略。雷公藤内酯醇（TPL）是从传统中药中分离得到的天然产物，具有较强的抗肿瘤活性。然而，其在焦亡中的作用仍有待阐明。通过集落形成测定来测量细胞存活。Annexin V法检测细胞凋亡;通过形态学特征以及白细胞介素1β和乳酸脱氢酶A（LDHA）的释放来评估焦亡。免疫荧光染色用于测量蛋白质的亚细胞定位。通过异种移植肿瘤模型评估致瘤性。mRNA或蛋白质的表达水平分别通过qPCR或蛋白质印迹测定来确定。雷公藤内酯醇通过诱导Gasdermin E（GSDME）介导的细胞凋亡作用消除头颈部癌细胞。沉默GSDME减弱了TPL对癌细胞的细胞毒性。TPL处理抑制癌细胞中c-myc和线粒体己糖激酶II（HK-II）的表达，导致BAD/BAX-胱天蛋白酶3级联的活化和活性胱天蛋白酶3对GSDME的裂解。沉默HK-II使癌细胞对TPL诱导的焦亡敏感，而HK-II的增强表达防止TPL诱导的焦亡。在机制上，HK-II防止BAD、BAX蛋白的线粒体易位和半胱天冬酶3的活化，从而减弱TPL处理后GSDME的切割和焦亡。此外，TPL治疗抑制NRF 2/SLC 7A 11（也称为xCT）轴，并诱导活性氧（ROS）积累，无论GSDME的状态如何。TPL与SLC 7A 11的抑制剂erastin的组合在体外和裸鼠模型中对肿瘤存活的抑制发挥稳健的协同作用。这项研究不仅提供了一个新的范例TPL在癌症治疗中，但也强调了线粒体HK-Ⅱ在连接葡萄糖代谢与焦亡的关键作用。在线版本包含补充材料，可通过10.1186/s13046-021-01995-7获得。
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. 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. Cell 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. Triptolide 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. This 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. The online version contains supplementary material available at 10.1186/s13046-021-01995-7.
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