PMID- 34108030 OWN - NLM STAT- MEDLINE DCOM- 20211228 LR - 20220420 IS - 1756-9966 (Electronic) IS - 0392-9078 (Print) IS - 0392-9078 (Linking) VI - 40 IP - 1 DP - 2021 Jun 9 TI - Natural product triptolide induces GSDME-mediated pyroptosis in head and neck cancer through suppressing mitochondrial hexokinase-IotaIota. PG - 190 LID - 10.1186/s13046-021-01995-7 [doi] LID - 190 AB - BACKGROUND: 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. METHODS: 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 1beta 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. RESULTS: 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. CONCLUSIONS: 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. FAU - Cai, Jing AU - Cai J AD - Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Tongzipo Road, Changsha, 410013, Hunan, China. AD - Hunan Key Laboratory of Nonresolving Inflammation and Cancer, The Third Xiangya Hospital, Central South University, Changsha, 410013, Hunan, China. AD - The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China. AD - The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and School of Basic Medical Sciences, Central South University, Changsha, 410078, Hunan, China. FAU - Yi, Mei AU - Yi M AD - The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China. AD - Department of Dermatology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China. FAU - Tan, Yixin AU - Tan Y AD - Department of Dermatology, Second Xiangya Hospital, Hunan Key Laboratory of Medical Epigenetics, The Central South University, Changsha, 410011, Hunan, China. FAU - Li, Xiaoling AU - Li X AD - Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Tongzipo Road, Changsha, 410013, Hunan, China. AD - Hunan Key Laboratory of Nonresolving Inflammation and Cancer, The Third Xiangya Hospital, Central South University, Changsha, 410013, Hunan, China. AD - The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China. AD - The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and School of Basic Medical Sciences, Central South University, Changsha, 410078, Hunan, China. FAU - Li, Guiyuan AU - Li G AD - Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Tongzipo Road, Changsha, 410013, Hunan, China. AD - Hunan Key Laboratory of Nonresolving Inflammation and Cancer, The Third Xiangya Hospital, Central South University, Changsha, 410013, Hunan, China. AD - The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China. AD - The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and School of Basic Medical Sciences, Central South University, Changsha, 410078, Hunan, China. FAU - Zeng, Zhaoyang AU - Zeng Z AD - Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Tongzipo Road, Changsha, 410013, Hunan, China. AD - Hunan Key Laboratory of Nonresolving Inflammation and Cancer, The Third Xiangya Hospital, Central South University, Changsha, 410013, Hunan, China. AD - The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China. AD - The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and School of Basic Medical Sciences, Central South University, Changsha, 410078, Hunan, China. FAU - Xiong, Wei AU - Xiong W AD - Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Tongzipo Road, Changsha, 410013, Hunan, China. AD - Hunan Key Laboratory of Nonresolving Inflammation and Cancer, The Third Xiangya Hospital, Central South University, Changsha, 410013, Hunan, China. AD - The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China. AD - The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and School of Basic Medical Sciences, Central South University, Changsha, 410078, Hunan, China. FAU - Xiang, Bo AU - Xiang B AUID- ORCID: 0000-0003-2641-5434 AD - Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Tongzipo Road, Changsha, 410013, Hunan, China. xiangbolin@csu.edu.cn. AD - Hunan Key Laboratory of Nonresolving Inflammation and Cancer, The Third Xiangya Hospital, Central South University, Changsha, 410013, Hunan, China. xiangbolin@csu.edu.cn. AD - The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China. xiangbolin@csu.edu.cn. AD - The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and School of Basic Medical Sciences, Central South University, Changsha, 410078, Hunan, China. xiangbolin@csu.edu.cn. LA - eng GR - 81772902, 81872278, 81703131, 82072596/National Natural Science Foundation of China/ GR - 2018JJ1040, 2020JJ4920, 2020JJ4838, 2020JJ4766, 2020JJ3055/Natural Science Foundation of Hunan Province/ PT - Journal Article DEP - 20210609 PL - England TA - J Exp Clin Cancer Res JT - Journal of experimental & clinical cancer research : CR JID - 8308647 RN - 0 (Biological Products) RN - 0 (Diterpenes) RN - 0 (Epoxy Compounds) RN - 0 (Immunosuppressive Agents) RN - 0 (Phenanthrenes) RN - 19ALD1S53J (triptolide) RN - EC 2.7.1.1 (HK2 protein, human) RN - EC 2.7.1.1 (Hexokinase) SB - IM EIN - J Exp Clin Cancer Res. 2021 Sep 22;40(1):298. PMID: 34551793 CIN - Cancer Lett. 2022 May 28;534:115568. PMID: 35131385 MH - Animals MH - Biological Products/pharmacology/*therapeutic use MH - Cell Line, Tumor MH - Diterpenes/pharmacology/*therapeutic use MH - Epoxy Compounds/pharmacology/therapeutic use MH - Head and Neck Neoplasms/*drug therapy MH - Hexokinase/*drug effects MH - Humans MH - Immunosuppressive Agents/pharmacology/*therapeutic use MH - Male MH - Mice MH - Mice, Nude MH - Mitochondria/*drug effects MH - Phenanthrenes/pharmacology/*therapeutic use MH - Pyroptosis/*drug effects MH - Transfection PMC - PMC8188724 OTO - NOTNLM OT - Ferroptosis OT - Gasdermins OT - Head and neck squamous cell carcinoma OT - Nasopharyngeal carcinoma OT - X(c)(-) cysteine/glutamate antiporter COIS- The authors declare no conflict of interests. EDAT- 2021/06/11 06:00 MHDA- 2021/12/29 06:00 PMCR- 2021/06/09 CRDT- 2021/06/10 05:45 PHST- 2021/01/28 00:00 [received] PHST- 2021/05/24 00:00 [accepted] PHST- 2021/06/10 05:45 [entrez] PHST- 2021/06/11 06:00 [pubmed] PHST- 2021/12/29 06:00 [medline] PHST- 2021/06/09 00:00 [pmc-release] AID - 10.1186/s13046-021-01995-7 [pii] AID - 1995 [pii] AID - 10.1186/s13046-021-01995-7 [doi] PST - epublish SO - J Exp Clin Cancer Res. 2021 Jun 9;40(1):190. doi: 10.1186/s13046-021-01995-7.