2. Academic Validation
  3. 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

  • J Exp Clin Cancer Res. 2021 Jun 9;40(1):190. doi: 10.1186/s13046-021-01995-7.
Jing Cai  # 1 2 3 4,  Mei Yi  # 3 5,  Yixin Tan 6,  Xiaoling Li 1 2 3 4,  Guiyuan Li 1 2 3 4,  Zhaoyang Zeng 1 2 3 4,  Wei Xiong 1 2 3 4,  Bo Xiang 7 8 9 10
Affiliations

Affiliations

  • 1 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.
  • 2 Hunan Key Laboratory of Nonresolving Inflammation and Cancer, The Third Xiangya Hospital, Central South University, Changsha, 410013, Hunan, China.
  • 3 The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
  • 4 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.
  • 5 Department of Dermatology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
  • 6 Department of Dermatology, Second Xiangya Hospital, Hunan Key Laboratory of Medical Epigenetics, The Central South University, Changsha, 410011, Hunan, China.
  • 7 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.
  • 8 Hunan Key Laboratory of Nonresolving Inflammation and Cancer, The Third Xiangya Hospital, Central South University, Changsha, 410013, Hunan, China. xiangbolin@csu.edu.cn.
  • 9 The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China. xiangbolin@csu.edu.cn.
  • 10 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.
  • # Contributed equally.
PMID: 34108030 DOI: 10.1186/s13046-021-01995-7
Abstract

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 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.

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.

Keywords

Ferroptosis; Gasdermins; Head and neck squamous cell carcinoma; Nasopharyngeal carcinoma; X(c)(−) cysteine/glutamate antiporter.

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