Natural product triptolide induces GSDME-mediated pyroptosis in head and neck cancer through suppressing mitochondrial hexokinase-ΙΙ
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...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2021-06-01
|
| Series: | Journal of Experimental & Clinical Cancer Research |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13046-021-01995-7 |
| _version_ | 1818836816623566848 |
|---|---|
| author | Jing Cai Mei Yi Yixin Tan Xiaoling Li Guiyuan Li Zhaoyang Zeng Wei Xiong Bo Xiang |
| author_facet | Jing Cai Mei Yi Yixin Tan Xiaoling Li Guiyuan Li Zhaoyang Zeng Wei Xiong Bo Xiang |
| author_sort | Jing Cai |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-19T03:12:37Z |
| format | Article |
| id | doaj.art-c1c12ba5700349b685a5725a38f19f0e |
| institution | Directory Open Access Journal |
| issn | 1756-9966 |
| language | English |
| last_indexed | 2024-12-19T03:12:37Z |
| publishDate | 2021-06-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj.art-c1c12ba5700349b685a5725a38f19f0e2022-12-21T20:37:58ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662021-06-0140111710.1186/s13046-021-01995-7Natural product triptolide induces GSDME-mediated pyroptosis in head and neck cancer through suppressing mitochondrial hexokinase-ΙΙJing Cai0Mei Yi1Yixin Tan2Xiaoling Li3Guiyuan Li4Zhaoyang Zeng5Wei Xiong6Bo Xiang7Hunan Provincial Cancer Hospital and Cancer Hospital Affiliated to Xiangya Medical School, Central South UniversityThe Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, Xiangya Hospital, Central South UniversityDepartment of Dermatology, Second Xiangya Hospital, Hunan Key Laboratory of Medical Epigenetics, The Central South UniversityHunan Provincial Cancer Hospital and Cancer Hospital Affiliated to Xiangya Medical School, Central South UniversityHunan Provincial Cancer Hospital and Cancer Hospital Affiliated to Xiangya Medical School, Central South UniversityHunan Provincial Cancer Hospital and Cancer Hospital Affiliated to Xiangya Medical School, Central South UniversityHunan Provincial Cancer Hospital and Cancer Hospital Affiliated to Xiangya Medical School, Central South UniversityHunan Provincial Cancer Hospital and Cancer Hospital Affiliated to Xiangya Medical School, Central South UniversityAbstract 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.https://doi.org/10.1186/s13046-021-01995-7Head and neck squamous cell carcinomaFerroptosisGasderminsNasopharyngeal carcinomaX(c)(−) cysteine/glutamate antiporter |
| spellingShingle | Jing Cai Mei Yi Yixin Tan Xiaoling Li Guiyuan Li Zhaoyang Zeng Wei Xiong Bo Xiang Natural product triptolide induces GSDME-mediated pyroptosis in head and neck cancer through suppressing mitochondrial hexokinase-ΙΙ Journal of Experimental & Clinical Cancer Research Head and neck squamous cell carcinoma Ferroptosis Gasdermins Nasopharyngeal carcinoma X(c)(−) cysteine/glutamate antiporter |
| title | Natural product triptolide induces GSDME-mediated pyroptosis in head and neck cancer through suppressing mitochondrial hexokinase-ΙΙ |
| title_full | Natural product triptolide induces GSDME-mediated pyroptosis in head and neck cancer through suppressing mitochondrial hexokinase-ΙΙ |
| title_fullStr | Natural product triptolide induces GSDME-mediated pyroptosis in head and neck cancer through suppressing mitochondrial hexokinase-ΙΙ |
| title_full_unstemmed | Natural product triptolide induces GSDME-mediated pyroptosis in head and neck cancer through suppressing mitochondrial hexokinase-ΙΙ |
| title_short | Natural product triptolide induces GSDME-mediated pyroptosis in head and neck cancer through suppressing mitochondrial hexokinase-ΙΙ |
| title_sort | natural product triptolide induces gsdme mediated pyroptosis in head and neck cancer through suppressing mitochondrial hexokinase ιι |
| topic | Head and neck squamous cell carcinoma Ferroptosis Gasdermins Nasopharyngeal carcinoma X(c)(−) cysteine/glutamate antiporter |
| url | https://doi.org/10.1186/s13046-021-01995-7 |
| work_keys_str_mv | AT jingcai naturalproducttriptolideinducesgsdmemediatedpyroptosisinheadandneckcancerthroughsuppressingmitochondrialhexokinaseii AT meiyi naturalproducttriptolideinducesgsdmemediatedpyroptosisinheadandneckcancerthroughsuppressingmitochondrialhexokinaseii AT yixintan naturalproducttriptolideinducesgsdmemediatedpyroptosisinheadandneckcancerthroughsuppressingmitochondrialhexokinaseii AT xiaolingli naturalproducttriptolideinducesgsdmemediatedpyroptosisinheadandneckcancerthroughsuppressingmitochondrialhexokinaseii AT guiyuanli naturalproducttriptolideinducesgsdmemediatedpyroptosisinheadandneckcancerthroughsuppressingmitochondrialhexokinaseii AT zhaoyangzeng naturalproducttriptolideinducesgsdmemediatedpyroptosisinheadandneckcancerthroughsuppressingmitochondrialhexokinaseii AT weixiong naturalproducttriptolideinducesgsdmemediatedpyroptosisinheadandneckcancerthroughsuppressingmitochondrialhexokinaseii AT boxiang naturalproducttriptolideinducesgsdmemediatedpyroptosisinheadandneckcancerthroughsuppressingmitochondrialhexokinaseii |